Supplementary Material 0114-5916/09/0007-0001/$49.95/0 REVIEW ARTICLE © 2009 Adis Data Information BV

Pharmacokinetic Changes of Psychotropic Drugs in Patients with Liver Disease Implications for Dose Adaptation

Chantal Schlatter,† Sabin S. Egger,† Lydia Tchambaz† and Stephan Krähenbühl

Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland

† These authors contributed equally to this work.

Supplementary Material

This supplementary material contains the table referred to in the full version of this article, which can be found at http://drugsafety.adisonline.com. Note the reference citations and reference list are independent from the published article and reference numbering will differ.

Table I. Kinetic data including metabolic pathway, hepatic and dose-dependent adverse effects and dose adjustment recommendations for the use of psychotropic drugs in patients with liver disease

b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Psychostimulants Am- Lo Deethylation 0.95 2 95 restlessness, dizzi- Studies: No clinical studies available in pa- fepramone of the amine ness, tremor, insom- tients with liver disease. Product information: function, nia, anxiety, delirium, Contraindicated in patients with liver failure. reduction of hallucinations, de- Personal recommendation: Should be the ketone pression, changes in avoided in patients with liver disease. function, libido, pallor or flush- and hy- ing, palpitation, ar- droxylation rhythmia, anginal pain, of the ben- hypertension, circula- zene ring[1-3] tory collapse, excessive sweating, dry mouth, anorexia[1]

Methyl- Hi Deesterifi- 0.95 2 20 2 30 40 0.7 Case re- nervousness, insom- Studies:recommendation: No clinical studies available in pa- phenidate cation by ports: nia, headache, dizzi- tients with liver disease. Product information: non micro- hepatocel- ness, dyskinesia, tics, No recommendations provided. Personal somal es- lular in- seizure, abdominal According to pharmacoki- terase to jury,[4] liver pain, nausea, ano- netic data, start with a third of normal dose. ritalinic acid, failure after rexia, tachycardia, Adjust maintenance dose according to dose- minor: oxi- high palpitation, increased dependent adverse reactions. dation, hy- doses.[5] blood pressure, ar- droxyla- rhythmia, visual dis- tion.[2] turbances[1, 2, 6] Pharma- cokinetic data are presented as mean values for both enantiomers of

2 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects methylphenidate. Modafinil[7] Lo Hydrolytic 0.95 10.5 62 0.9 40-65 3.4 0.06 Sporadic: headache, anxiety Studies: In an open-label study, 21 patients deamida- elevated nervousness, insom- with primary biliary cirrhosis received modaf- tion, S- liver en- nia, dizziness, nau- inil at an initial dose of 100mg/d for treatment oxidation, zymes, sea, diarrhoea, ano- of daytime somnolence and fatigue.[9] Dos- aromatic cholestatic rexia, dry mouth, con- age was up-titrated according to tolerability ring hy- liver injury[1, stipation, changes in and response. Significant reduction in day- droxylation, 3] blood pressure, extra- time somnolence and fatigue were observed. glucuronida- systoles, palpitations, Seven patients discontinued treatment due tion.[3] tachycardia, arrhyth- toformation: significant headache. No major increase in mias[1, 8] blood pressure was observed. Product in- Caution in patients with severe liver disease. T1/2 is doubled in patients with liver cirrhosis. 50% dose reduction in patients with severe liver disease to 100- 200mg/d. Personal recommendation: Ac- cording to pharmacokinetic data, open-label study and product information, start with 100mg daily and adjust dosage according to dose-dependent adverse reactions. Phenter- Nk Mainly renal 0.3 20 3.5 restlessness, dizzi- Studies:mation: No clinical studies available in pa- mine elimination, ness, tremor, insom- tients with liver insufficiency. Product infor- 5% metabo- nia, anxiety, hallucina- Contraindicated in patients with liver lized by N- tions, changes in li- insufficiency. Personal recommendation: oxidation, bido, palpitation, ar- According to pharmacokinetic data showing entero- rhythmia, anginal pain, primarily renal elimination, dosage should be hepatic hypertension, circula- adjusted according to renal function. circulation[1] tory collapse, excessive sweating, dry mouth, gastrointestinal symptoms[1]

3 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Phenylpro- Lo Renal elimi- 0.15 4 4 99 restlessness, dizzi- Studies: No clinical studies available in pa- panolamine nation[1] ness, tremor, insom- tients with liver disease. Product information: nia, anxiety, aggres- Contraindicated in patients with liver failure. siveness, irritability, Personal recommendation: According to changes in libido, pharmacokinetic data, showing primarily palpitation, tachycar- renal elimination, dosage should be adjusted dia, anginal pain, hy- according to renal function. pertension, excessive sweating, dry mouth, anorexia, gastrointestinal symptoms[1] Sibutramine Hi Demethyla- 1 1.1 97 1750 >0.9 frequency tachycardia, palpita- Studies: No clinical studies available in pation (CYP unknown: tions, hypertension, tients with liver disease. Product information: 3A4) to abnormal constipation, anorexia, Combined AUC of the two active metabolites active liver func- nausea, dry mouth, increased by 24% in patients with moderate mono- tion tests insomnia, headache, liver insufficiency compared with healthy desmethyl- (ALT, AST, dizziness[1, 3, 10] subjects. No dosage adjustment necessary and di- AP);[3] case in patients with mild to moderate liver im- report: desmethyl- cho- pairment.mendation: Contraindicated in patients with sibutramine, lestatic severe liver dysfunction. Personal recom- followed by hepatitis.[11] According to pharmacokinetic hydroxyla- data, start with the lowest possible dose tion and available (10mg/d). Adjust maintenance conjuga- dose according to dose-dependent adverse tion,[1, 8] reactions. enterohepatic circulation.[10] Antiepileptics

4 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Barbexa- Lo Hydroxyla- 0.75 80 50 0.7 90 0.3 <0.01 Induction of Irritability, agitation, Studies: Mean t1/2 of phenobarbital was sig- clone tion to hy- acute in- drowsiness, optical nificantly prolonged by 51% in cirrhotics droxyphe- termittent hallucinations, ataxia, compared with healthy individuals (130 vs 86 [1] [13] nobarbital porphyria. nystagmus, dizziness, hours). T1/2 of phenobarbital was not sig- (inactive).[12] vomiting, weight loss, nificantly different between patients with Note: Bar- gingival hyperplasia, acute viral hepatitis and healthy individuals [13] bexaclon is respiratory depres- (104information: vs 86 hours). Monitoring of serum a salt com- sion, hypotension, levels recommended in patients with liver posed of shock, rhabdomyoly- disease and prolonged therapy.[13] Product phenobarbi- sis[1] Contraindicated in patients with tal and L- severe liver disease. Adjust dosage in pa- propylhexe- tientsmendation: with liver disease (no specification) drine. The and monitor serum levels. Personal recom- listed kinetic According to pharmacokinetic data refer to data, start with dose in the lower range of phenobarbi- normal. Adjust maintenance dose according tal. to the measured therapeutic concentration (therapeutic range: 10-40 mg/L). Car- Lo Epoxidation 1 15 75 1.4 >70 4.5 0.08 Frequent: dizziness, drowsiness, Studies: No clinical studies available in pa- bamazepine to active hepatocel- unsteadiness, head- tients with liver disease. Product information: epoxide lular injury ache, ataxia, diplopia, Cautionrecommendation: in patients with liver disease. Moni- metabolite (increase of nausea, vomiting, tor liver function and stop carbamazepine in by CYP transami- asthenia, tremor, dy- case of worsening liver function. Personal 3A4, glu- nases). skinesia, oedemas, According to pharmacoki- Rare: curonida- cho- weight gain, SIADH, netic data, start with initial dose in the lower tion, further lestatic liver tachycardia, hypoten- range of normal and adjust maintenance metabolism injury. Very sion, arrhythmia, res- dose according to plasma concentrations of rare: of active granu- piratory depression[1, 2, carbamazepine (therapeutic range: 4-11 metabolite lomas, liver 8] mg/L). by epoxide failure.[1, 4] hydrolase.[2] Induction of acute in- termittent porphyria.[1]

5 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Clonaze- Lo CYP 3A4,[14] 1 30 85 3 98 6.5 0.12 Rare: hepa- drowsiness, dizziness, Studies: PB reduced in cirrhotic patients.[15] pam nitro-group tocellular muscular weakness, Patients with liver cirrhosis may be sensitive reduction, injury.[4] ataxia, dysarthria, tosonal sedative recommendation: effects of benzodiazepines.[16] N- constipation, coordina- Product information: Clonazepam should not acetylation disturbances, be used in patients with liver cirrhosis. Per- tion.[2] diplopia, nystagmus, According to phar- hypotension, respira- macokinetic data, start with low initial dose tory depression[1, 2, 8] and adjust maintenance dose according to clinical effect and dose-dependent adverse effects. Etho- Lo Oxidation,[2] 0.8 45 5 0.7 100 0.7 0.01 nausea, vomiting, Studies:sonal recommendation: No clinical studies available in pa- suximide CYP 3A4 anorexia, diarrhoea, tients with liver disease. Product information: and CYP hiccup, behavioural Caution in patients with liver disease. Per- 2E1 (mi- changes, seizures, According to phar- nor)[17] drowsiness, head- macokinetic data, start with an initial dose in ache, dizziness, the lower range of normal and adjust main- ataxia, photophobia[1, tenance dose according to dose-dependent 2] adverse reactions. Gabapentin Lo Not metabo- 0.01 6.5 0 0.8 60 6.7 0.01 Case re- drowsiness, dizziness, Studies: No clinical studies available in pa- recommendation: lized, ex- ports: acute asthenia, somnolence, tients with liver disease. Product information: creted un- hepatotox- unsteadiness, amne- No recommendation provided. Personal changed in icity with sia, ataxia, tremor, Monitor creatinine clear- the urine.[1] mixed pat- nystagmus, diplopia, ance and adjust maintenance dose accord- tern (in- dry mouth, constipa- ingly. crease in tion, weight gain, oe- aminotrans- dema[1, 2] ferases, γGT and AP),[18] cholestatic liver injury.[19]

6 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Lamotrigine Lo N- 0.9 30 55 1.1 98 2 0.03 Case re- dizziness, ataxia, Studies: Pharmacokinetic parameters were glucuronida- port: case somnolence, fatigue, comparable between healthy controls and tion.[2] of mixed headache, irritability, patients with liver cirrhosis Child-Pugh class liver in- agitation, insomnia, A.[21] Oral clearance was reduced by 40% jury,[20] diplopia, nystagmus, and 64% in patients with cirrhosis Child- impaired tremor, arthralgia, Pugh class B and C, respectively. T1/2 in- liver func- blurred vision, nausea, creased 2 and 3 times and AUC was 80% tion, liver vomiting[1, 2] and 197% higher compared with controls. [1] failure. Recommendationinformation: to reduce initial and maintenance dose by 50 or 75% in patients with cirrhosis Child-Pugh class B or C. Product In a single dose pharmacokinetic study clearance in patients with liver cirrhosis Child-Pugh class A, B and C was 9%, 29% and 71% lower compared with healthy volunteers. Initial, escalation and maintenance dose should therefore be reduced by 50% in patients with liver cirrhosis Child-Pugh class B and by 75% with Child- Pugh class C. Personal recommendation: According to pharmacokinetic data and clinical studies, initial dose should be reduced by 50% and 75% in patients with cirrhosis Child-Pugh B and C, respectively. Adjust maintenance dose carefully according to clinical response and dose-dependent adverse effects. Plasma concentrations may be helpful.

7 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Leveti- Lo enzymatic 0.3 7 5 0.6 100 4 0.02 Postmar- somnolence, drowsi- Studies: Pharmacokinetics of levetiracetam racetam hydrolysis of keting re- ness, asthenia, confu- and its metabolite do not differ between the ports: sion, dizziness, in- healthy subjects and those with class A or B acetamide hepatitis, somnia, irritability, cirrhosis.[22] In patients with liver cirrhosis group, renal abnormal nervousness, depres- Child-Pugh class C total clearance is re- elimina- liver func- sion, ataxia, tremor, duced by 57% probably due to a deteriora- tion.[1] tion tests.[1] diplopia, diarrhoea, tion of renal function in most patients with nausea[1, 8] severe hepatic disease. No dosage adjustment necessary in patients with mild to moderate liver impairment (Child-Pugh class A and B). Patients with class C cirrhosis should initially receive only half of the recommended dose.[22] Product information: Levetiracetam dose should initially be reduced by 50% in patients with severe cirrhosis (Child-Pugh class C) and creatinine clearance <70 ml/min. Personal recommendation: Monitor creatinine clearance and adjust maintenance dose accordingly. Meth- Nk Oxidation, 1 2.5 May pre- nausea, vomiting, Studies: No clinical studies available in pa- suximide hydroxyla- cipitate hiccup, seizures, tientssonal withrecommendation: liver disease. Product information: tion, N- hepatic drowsiness, head- Caution in patients with liver disease, moni- demethyla- acute por- ache, dizziness, toring of liver function recommended. Per- tion to ac- phyria.[23] blurred vision, diplo- Because of lack of tive metabo- pia, ataxia, photopho- pharmacokinetic data, no dose recommen- lite (N- bia[1] dations can be made. desmethyl- suximide).[1]

8 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Oxcar- Hi 10-keto 1.0 OXC: 40 0.7 283 >0.9 Sporadic: sedation, dizziness, Studies: No clinical studies available in pa- bazepine reduction 2, MHD MHD OXC OXC elevation of drowsiness, diplopia, tients with liver disease. Product information: (cytosolic MHD: γGT.[25] nystagmus, ataxia, No difference in pharmacokinetic parameters arylketone 9 Very rare: headache, nausea, of oxcarbazepine and MHD observed in pa- reductase) hepatocel- vomiting, tremor, ab- tients with mild to moderate liver disease of oxcar- lular in- normal gait, depres- compared with healthy individuals after ad- bazepine jury.[1] sion, hyponatremia[1, 8] ministration of oxcarbazepine 900mg as a (OXC) to single dose. No data available in patients monohy- with severe liver insufficiency. Dose adjust- droxy de- mentssonal recommendation:not required in patients with mild to rivative moderate hepatic impairment. Caution in (MHD, ac- patients with severe liver insufficiency. Per- tive).[24] Because of missing MHD is data concerning bioavailability and clearance cleared by of the active metabolite, no dose recommen- glucuronida- dation according to pharmacokinetics can be tion and made. Follow the recommendations from the oxidation.[24] product information. Avoid in patients with About 27% severe liver disease. eliminated as MHD in urine.

9 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Phenobarbi- Lo Oxidation 0.75 80 50 0.7 90 0.3 <0.01 Sporadic: drowsiness, dizziness, Studies: Mean t1/2 of phenobarbital was pro- tal (CYP hepatocel- lethargy, headache, longed by 51% in cirrhotics compared with [13] 2C19), glu- lular injury, neuralgia, nausea, healthy individuals (130 vs 86 hours). T1/2 curonida- cholestatic vomiting, ataxia, nys- of phenobarbital was not significantly differ- tion.[2] liver in- tagmus, diplopia, res- ent between patients with acute viral hepati- jury.[4] In- piratory depression, tis and healthy individuals (104 vs 86 duction of arrhythmia, bradycar- hours).[13] Monitoring of plasma levels rec- acute in- dia, hypotension, ommended in patients with liver disease and termittent rhabdomyolysis[1, 2] prolonged therapy.[13] Product information: In porphyria.[1] patients with severe liver disease, it may be contraindicated, in particular if serum levels tion: are not monitored. Personal recommenda- According to pharmacokinetic data, start with dose in the lower range of normal and adjust maintenance dose according to the measured therapeutic concentration (therapeutic range: 10-40 mg/L). Phenytoin Lo Hydroxyla- 1 24 90 0.7 90 var Rare: hepa- nys- : Increased fraction (one-third) of acute overdose: Studies tion (CYP tocellular or tagmus, diplopia, unbound phenytoin in patients with acute 2C9, CYP mixed liver ataxia, dizziness, viral hepatitis, however no change in t1/2 or 2C19), glu- injury, tremor, mental confu- plasma clearance.[26] No dose adjustment curonida- granu- sion, nausea, vomit- necessary in patients with acute viral hepati- tion.[1] loma.[4] ing, drowsiness, stu- tis.mation:[26] Patients with hepatic disease may Saturable por, respiratory and show early signs of toxicity.[8] Product infor- metabolism circulatory depression; Because of inter-individual pharma- with thera- chronic overdosage: cokinetics dosage has to be adjusted ac- peutic intellectual dulling, cording to the therapeutic concentration [10- doses. Un- depression of mood, 20mg/L]. Personal recommendation: Start dergoes dyskinesia, gingival with initial dose in the lower range of normal. entero- hyperplasia, hyper- Adjust maintenance dose according to hepatic trichosis, hypergly- measured serum concentration. In case of circulation.[1] caemia, hypocalcae- hypoalbuminemia adjust maintenance dose mia, folate depletion, according to the measured free concentra- peripheral polyneuro- tion. pathy[1, 2]

10 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Pregabalin Lo Metabolism 0.02 6.3 0 0.56 90 3.4 <0.01 Occasion- dizziness, somno- Studies: No clinical studies available in pa- negligible, ally: mod- lence, confusion, tients with liver disease. Product information: renal elimi- est and ataxia, impaired con- Because of mainly renal elimination no sig- nation.[1] transient centration, incoordina- nificant changes in pregabalin plasma con- elevation of tion, tremor, dy- centrations expected. No dose adjustment liver en- sarthria, blurred vi- necessary. Personal recommendation: Moni- zymes.[3] sion, diplopia, dry tor creatinine clearance and adjust mainte- mouth, constipation, nance dose accordingly. Avoid in patients oedema, weight gain, with liver disease. asthenia[1, 3] Primidone Lo Oxidation to 0.6 10 20 0.6 90 2 0.02 Case re- drowsiness, weak- Studies: Kinetics not changed in patients phenobarbi- port: coma ness, dizziness, with acute viral hepatitis.[27] The metabolite tal and con- reported in ataxia, nystagmus, phenylethylmalonamide were undetectable version to one patient nausea, vomiting, in all but one of the patients. Phenobarbital phenylethyl on pheno- impaired sexual func- could not be measured. No dose adjustment malonamide barbital and tion, decreased libido, required in patients with acute viral hepati- (active me- primidone difficulties with mem- tis.[27] Product information: Contraindicated in tabolites with acute ory and concentration, patients with severe liver insufficiency.[1] with longer hepatitis.[2] impaired fine motor Since pharmacokinetics of primidone in pa- t1/2 than Very rare: performance, respira- tients with liver disease may be changed, primi- hepatocel- tory depression[1, 2] dose adjustment is recommended (no speci- done).[2] lular in- fication).[1] Monitoring of serum levels may jury.[4] In- be helpful.[2] Personal recommendation: Ac- duction of cording to the pharmacokinetic data, start acute in- with an initial dose in the lower range of termittent normal and adjust maintenance dose ac- porphyria.[1] cording to dose-dependent adverse reactions (cave: active metabolites with longer t1/2 than primidone). Monitor serum levels. Sulthiame Nk Hydroxyla- 0.7 9 29 Case re- paraesthesia, tachyp- Studies: No clinical studies available in pa- [1] recommendation: tion port: eleva- noea, hyperpnoea, tients with liver disease. Product information: tion of ami- dyspnoea, dizziness, No recommendation provided. Personal notrans- headache, stenocar- Because of lack of phar- ferases.[28] dia, tachycardia, dip- macokinetic data, no dose recommendations lopia, singultus, weight can be made. loss, loss of appetite, nausea, vomiting[1]

11 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Tiagabine Lo Oxidation 0.99 8 96 1 90 4.3 0.08 dizziness, asthenia, Studies: Increase in AUC by 60% (unbound (CYP 3A4) drowsiness, somno- drug: 38%) in patients with cirrhosis Child- and glu- lence, nausea, diar- Pugh class A and 70% (unbound drug: curonida- rhoea, nervousness, 143%) with Child-Pugh class B; prolongation tion, entero- irritability, tremor, diffi- of t1/2 by 80% and 145%, respectively.[29] hepatic culty with concentra- Cmax increased by 47%, in both groups of circulation.[1, tion, depression, sei- patients with liver impairment compared with 29] [1, 3] zures, amblyopia healthy subjects (Cmax unbound drug: +32% Child-Pugh class A, +117% Child-Pugh class B). More neurological adverse effects in patients with liver disease: dizziness, tremor, nausea, somnolence, incoordination (study dosage 4mg twice a day).[29] Reduce dosage or prolong dosage interval (no specific recommendation). Product information: In patients with mild to moderate liver impairment dosesonal reduction recommendation: and/or prolongation of dosage interval is indicated. Contraindicated in patients with severe liver insufficiency. Per- Start with initial dose in the lower range of normal. Slow up- titration according to dose-dependent adverse reactions. Monitor patients for neurological adverse effects. Because of a higher incidence of neurological adverse effects, avoid in patients with severe liver disease. Topiramate Lo Renal elimi- 0.1 21 15 0.6 80 1.5 <0.01 Case re- somnolence, fatigue, Studies: No clinical studies available in pa- nation.[1] port: liver dizziness, ataxia, tients with liver disease. Product information: failure,[30] speech disorders, Reduced plasma clearance in patients with increase in nausea, paraesthesia, moderate and severe liver disease (no speci- transami- difficulty with concen- fication). Caution in patients with liver dis- nases.[3] tration and attention, ease. Personal recommendation: Monitor mood disorders, con- creatinine clearance and adjust maintenance fusion, depression, dose accordingly. nervousness, diplopia, anorexia, weight loss[1, 3]

12 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Valproic Lo Glucuroni- 0.95 14 90 0.2 100 0.5 <0.01 Frequent: somnolence, drowsi- Studies: T1/2 was prolonged by factor 1.5 acid dation transient ness, hyperactivity, (from 12 to 19h), PB decreased by 20% and (approx. increase in irritability, ataxia, as- Vd increased by 1.5 in patients with cirrhosis 50%), beta- aminotrans- thenia, tremor, nau- compared with healthy subjects.[33] The ef- oxidation ferases. sea, vomiting, diar- fects were more pronounced in patients with (approx. Rare: acute rhoea, hyperam- alcoholic cirrhosis than in those recovering 40%), CYP liver failure monaemia, thrombo- from acute hepatitis. Total plasma clearance (approx. with mi- cytopenia, alopecia, was not significantly altered, whereas un- 10%),[2, 31] crovesicular weight gain[1, 2] bound drug clearance was significantly re- biliary ex- steatosis duced in cirrhotics compared with controls cretion and/or (38.5 vs 77.4 ml/min). Valproate should not (rat).[2] zonal ne- be used in patients with mitochondrial dis- crosis,[32] eases.[34] Product information: Contraindi- hepatocel- cated in patients with acute and chronic lular and/or hepatitis, severe hepatitis in the family his- cholestatic tory (especially drug-induced hepatitis), he- liver in- patic porphyria. Personal recommendation: jury.[3] According to the pharmacokinetic data, start with an initial dose in the lower range of normal and adjust maintenance dosage according to plasma concentration [therapeutic concentrations: 50-100mg/L]. In case of hypoalbuminemia adjust dosage according to the free valproate concentration (potential dose reduction up to 50%). Monitor liver function. Vigabatrin Lo Renal elimi- 0.01 7 0 1 5.6 <0.01 Case re- somnolence, drowsi- Studies: No clinical studies available in pa- nation.[1] port: liver ness, dizziness, tients with liver disease. Product information: failure.[35] headache, depres- No dose adjustment recommendations pro- sion, ataxia, confu- vided. Personal recommendation: Monitor sion, agitation, nerv- creatinine clearance and adjust maintenance ousness, irritability, dose accordingly. hyperkinesia, nystagmus, diplopia, tremor, paraesthesia, seizures, weight gain[1, 2] Anti-Parkinson drugs

13 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Amantadine Lo Renal elimi- 0.1 15 67 7.5 90 17.5 0.03 Rare: re- insomnia, dizziness, Studies: No clinical studies available in pa- nation.[2] versible nervousness, nausea, tients with liver disease. Product information: elevation of headache, anxiety, Shouldtion: be used with caution in patients with liver en- depression, confusion, severe liver disease. Personal recommenda- zymes (no hallucinations, ataxia, Monitor creatinine clearance and adjust specifica- slurred speech, ano- maintenance dose accordingly. tion).[1, 8] rexia, anticholinergic None.[4] effects (dry mouth, constipation, urinary retention), orthostatic hypotension, convulsions, arrhythmia[1, 8] Biperiden Hi Hydroxyla- 1 18 95 24 33 48.7 0.9 drowsiness, dizziness, Studies: No clinical studies available in pa- [2] recommendation: tion headache, agitation, tients with liver disease. Product information: anxiety, confusion, No recommendation provided. Personal impaired memory, According to pharmacoki- hallucinations, periph- netic data, initial doses should be reduced by eral anticholinergic at least 50%. Adjust maintenance dose ac- effects (dry mouth, cording to dose-dependent adverse reac- mydriasis, blurred tions. vision, urinary retention, decreased sweating, constipation), tachycardia, hypotension, convulsions[1, 2]

14 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Bro- Hi pH- 1 7 96 2 6 56 >0.9 Case re- nausea, vomiting, Studies: No clinical studies available in pa- mocriptine dependent ports: dizziness, drowsiness, tients with liver disease. Product information: epimeriza- hyper- orthostatic hypoten- Contraindicated in patients with severe liver tion at C-8, bilirubinae- sion, diarrhoea, head- disease. Personal recommendation: Accord- followed by mia.[4] ache, confusion, hal- ing to pharmacokinetic data, start with lowest oxidation, lucinations, dyskine- possible dose (1.25mg). Adjust maintenance oxidative sia, dry mouth, dose according to clinical effect and dose- ring open- paraesthesia[1, 2] dependent adverse effects. ing, and formation of 2-bromo- lysergic acid. Biliary elimination of metabolites (probably not active).[2, 36] Metabolism via CYP 3A4.[37] Cabergoline Hi Hydrolysis 0.98 65 41 1240 192 >0.9 Occasion- somnolence, fatigue, Studies: No clinical studies available in pa- of urea moi- ally: ab- dizziness, depression, tients with liver disease. Product information: ety (major), normal liver hallucination, confu- In 12 patients with mild-to-moderate hepatic oxidation, function sion, psychosis, hy- dysfunction, no significant effects on phar- deallylation, tests (ele- potension, nausea, macokinetic parameters were observed.[8] CYP 450 vations of vomiting, constipa- However, in patients with Child-Pugh class C [1, 2, 8] mediated bilirubin tion cirrhosis increase in Cmax and AUC were metabolism and significant. Contraindicated in patients with is minimal,[1, transami- severe liver insufficiency and cholestasis.[1] 2, 8] entero- nases).[1, 3] Adjust dosage (no specification) and monitor hepatic liver function. Personal recommendation: circulation.[1] According to pharmacokinetic data, start with lowest possible dose (0.5mg) and adjust maintenance dose according to clinical effect and dose-dependent adverse reactions. Caution in patients with cholestatic liver disease, as cabergoline is eliminated by biliary

15 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects excretion. Dihydroer- Hi CYP 3A4, 0.97 14 50 22 2.4 83.3 >0.9 dizziness, anxiety, Studies: No clinical studies available in pa- gocryptine biliary ex- headache, heartburn, tients with liver disease. Product information: cretion.[1] constipation, nausea, After administration of 20mg dihydroergoc- vomiting, asthenia, ryptine mesilate AUC and Cmax increased by orthostatic hypoten- 248% and 178% in patients with liver cirrho- sion, tachycardia[1] sis (Child-Pugh class A and B). Dihydroer- gocryptine is contraindicated in patients with liver cirrhosis Child-Pugh class C. Dosage reduction is required in patients with liver cirrhosis Child-Pugh class A and B (no specification). Personal recommendation: Start with lowest possible dose (5mg) and adjust maintenance dose according to clinical effect and dose-dependent adverse effects. Caution in patients with cholestatic liver disease, as dihydroergocryptine is eliminated by biliary excretion. Entacapone Hi Main meta- 1 0.5 98 2.6 35 48 0.9 Rare: ele- dyskinesia, hyperkine- Studies: No clinical studies available in pa- bolic path- vation of sia, dystonia, nausea, tients with liver disease. Product information: way is liver en- vomiting, constipation, 2-fold higher AUC and Cmax in patients with a isomerisa- zymes (no diarrhoea, urine dis- history of alcoholism and hepatic impairment tion to the specifica- coloration, abdominal after a single dose of entacapone.[8] Metabo- cis-isomer, tion), cho- pain, insomnia, hallu- lism of entacapone is decreased in patients followed by lestatic liver cinations, confusion, with liver cirrhosis Child-Pugh class A or B, direct glu- disease.[1] fatigue, dry mouth, and plasma concentrations are increased.[1] curonidation increased sweating[1, 8] Entacapone is contraindicated in patients of the par- with moderate and severe liver insuffi- ent and cis- ciency.[1] Personal recommendation: Accord- isomer,[3] ing to pharmacokinetic data, start with lowest eliminated possible initial dose (200mg) and adjust primarily by maintenance dose according to dose- biliary ex- dependent adverse effects. Caution in pa- cretion.[38] tients with cholestatic liver disease, as biliary elimination appears to be the major route of excretion.

16 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Levodopa Hi Decarboxy- 1 1.4 5 1 25 96.6 >0.9 Frequent: dyskinesia, nausea, Studies: No clinical studies available in pa- lation by higher lower elevation of vomiting, anorexia, tients with liver disease. Product information: dopa decar- with with AST levels abdominal pain, diar- Caution in patients with severe liver disease. boxylase to DDCI DDCI (incidence rhoea, constipation, Monitor liver function, especially at beginning dopamine 9%).[4] Also dry mouth, agitation, of therapy. In patients with moderate liver (active) and elevations anxiety, hallucinations, dysfunction dose adjustment may not be O- of ALT, AP, sleep disturbances, necessary. Personal recommendation: Ac- methylation and headache, drowsi- cording to pharmacokinetic data, start with by catechol- bilirubin ness, confusion, or- lowest dose of preparations containing O- reported.[3] thostatic hypotension, levodopa combined with dopa decarboxylase methyltrans- Case re- cardiac arrhythmia[1, 8] inhibitor. Adjust slowly according to clinical ferase to 3- ports: two effect and dose-dependent adverse reac- O- cases of tions. methyl- mixed liver dopa.[2] injury with Given to- jaundice gether with reported.[4] a dopa decarboxylase inhibitor (DDCI). Pergolide[39] Hi CYP 3A4, 1 27 90 24 105 >0.9 dyskinesia, hallucina- Studies: No clinical studies available in pa- oxidation to tions, confusion, som- tients with liver disease. Product information: pergolide nolence, insomnia, Caution in patients with liver insufficiency. sulfoxide nausea, constipation, Personal recommendation: Start with the and per- diarrhoea, dyspepsia, lowest possible dose as recommended in the golide sul- orthostatic hypoten- product information and adjust maintenance fone (both sion, arrhythmia[1, 2] dose according to dose-dependent adverse active in effects. Slower up-titration is recommended animals), in patients with liver disease. hydroxylation.[1, 2, 37]

17 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Pramipexole Lo Renal elimi- 0.15 8 15 7.1 90 30 0.08 Rare: ele- nausea, dizziness, Studies: No clinical studies available in pa- nation.[1] vation of hypotension, dyskine- tients with liver disease. Product information: transami- sia, extrapyramidal In case of liver disease probably no dose nase lev- movements, insomnia, adjustment necessary, because about 90% els.[40] restlessness, halluci- of pramipexole are eliminated through the nations, dream ab- kidneys. Personal recommendation: Accord- normalities, confusion, ing to the pharmacokinetic data, monitor constipation, asthenia, creatinine clearance and adjust maintenance somnolence, dry dose accordingly. mouth, amnesia[1, 3] Procyclidine Lo Hydroxyla- nk 12 1 75 4.1 drowsiness, dizziness, Studies: No clinical studies available in pation of the agitation, confusion, tients with liver disease. A twice daily dosage cyclohexane impaired memory, insteadsonal recommendation: of the usual thrice daily dosage had ring, oxida- hallucinations, periph- been suggested.[41] Product information: tion of the eral anticholinergic Caution in patients with liver disease. Per- benzyl effects (dry mouth, According to the ring.[2] mydriasis, blurred pharmacokinetic data, start with an initial vision, urinary reten- dose in the lower range of normal. Adjust tion, decreased sweat- maintenance dose according to dose- ing, constipation), dependent adverse reactions. tachycardia, hypotension, convulsions[1, 2] Ropinirole Me CYP 1A2 0.8 6 10- 7.5 55 47 0.7 Very rare: hallucination, somno- Studies: No clinical studies available in pa- (major), 3A 40 increase in lence, asthenia, dizzi- tients with liver disease. Product information: (minor). N- liver en- ness, dyskinesia, syn- Contraindicatedommendation: in patients with liver disease despropyla- zymes.[1] cope, hypotension, due to lack of clinical studies. Personal rec- tion, hy- nausea, vomiting, According to pharmacokinetic droxyla- oedema[1-3, 8] data, start with lowest recommended initial tion.[1, 2] dose. Adjust maintenance dose according to dose-dependent adverse reactions.

18 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Selegiline[42] Hi Oxidative 1 1.5 94 4.3 10 >54 >0.9 Sporadic: insomnia, dizziness, Studies: No clinical studies available in pa- recommendation: dealkylation (SD) elevation of hallucinations, agita- tients with liver disease. Product information: (CYP 1A2, liver en- tion, confusion, head- No recommendation provided. Personal CYP 3A4) to zymes (no ache, abnormal According to the pharma- ampheta- specifica- movements, nausea, cokinetic data, start with lowest initial dose mine, tion).[1] vomiting, gastrointes- (5mg/d). Adjust maintenance dose according metham- tinal ulcerations, dry to clinical effect and dose-dependent ad- phetamine mouth, urinary reten- verse reactions. and des- tion, orthostatic hy- methylse- potension, arrhyth- legiline.[2, 43] mia[1, 2, 8] Tolcapone Lo glucuronida- 0.99 2 99.9 0.13 65 7 0.13 Frequent: dyskinesia, sleep dis- Studies: After oral administration Cmax (29% tion (major), elevation of turbance, hallucina- and 35%) and AUC (17% and 21%) were methylation aminotrans- tion, dystonia, head- slightly higher among patients with non- by COMT to ferases; ache, nausea, vomit- cirrhotic and cirrhotic liver disease compared 3-O-methyl- unknown ing, diarrhoea, ano- with healthy subjects.[44] Bioavailability and tolcapone, frequency: rexia, dry mouth, in- t1/2 were not changed. Fraction unbound was hydroxyla- fulminant creased sweating, increased in cirrhotics due to lower albumin tion (CYP hepatitis, hypotension, syn- levels (0.2% vs 0.12% in controls). After i.v.- [1, 3, 8] 3A4, 2A6) liver fail- cope administration clearance and Vd of unbound followed by ure.[1] tolcapone was lower among patients with oxidation, cirrhosis than controls (45% and 35%).[44] reduction Halftion: of the recommended dosage should be (minor) to administered to cirrhotics. Product informa- an amine Due to the risk of severe liver injury, and subse- tolcapone is contraindicated in patients with quent N- liver disease and/or levels of ALT or AST acetyla- higher than the upper the limit of normal. No tion.[1, 8] pharmacokinetic changes were observed in patients with moderate non-cirrhotic liver disease. In patients with moderate liver cir- rhosistion: elimination of unbound tolcapone was decreased by 50%. Personal recommenda- Due to the risk of hepatic adverse effects tolcapone should not be used in patients with liver disease. Antipsychotics

19 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Amisul- Me Hydroxyla- 0.5 12 16 5.8 48 36.4 0.34 Very rare: extrapyramidal reac- Studies: No clinical studies available in pa- pride[45] tion, oxida- elevation of tions (pseudoparkin- tients with liver disease. Product information: tion of tetra- liver en- sonism, acute dyski- Dose reductions in patients with liver im- hydropyrrol zymes, nesia, dystonia, pairment should not be necessary as the ring, N- mainly of akathisia, tardive dy- drug undergoes only modest hepatic me- dealkyla- transami- skinesia), insomnia, tabolism. Personal recommendation: Accord- tion.[46] nases.[1] drowsiness, dizziness, ing to the pharmacokinetic data, start with a anxiety, depression, dosage in the lower range of normal and headache, seizures, adjust dosage according to dose-dependent galactorrhoea, adverse effects. amenorrhea, gynaecomastia, decreased libido, weight gain, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation), hypotension, bradycardia, arrhythmia, prolongation of QT interval (risk for torsade de pointes)[1] Aripiprazole Lo Dehydroge- 0.99 59 99 4.9 87 3.5 0.06 sporadic: somnolence, drowsi- Studies: No clinical studies available in pa- nation and elevations ness, asthenia, leth- tients with liver disease. Product information: hydroxyla- in transa- argy, insomnia, ex- No differences in pharmacokinetic parame- tion by CYP minases.[3] trapyramidal symp- ters of aripiprazole and its main metabolite 3A4 and toms (e.g. dystonia, dehydroaripiprazole observed after admini- CYP 2D6, pseudoparkinsonism, stration of a single dose of 15mg aripiprazole N- akathisia, acute dyski- tosonal patients recommendation: with liver cirrhosis Child-Pugh dealkylation nesia, tardive dyski- class A, B or C. Dosage adjustment is not by CYP nesia), seizures, nau- required in patients with liver disease. Per- 3A4.[1, 47] sea, vomiting, consti- According to the Major me- pation, weight gain, pharmacokinetic data start with doses in the tabolite blurred vision, or- lower range of normal and adjust mainte- dehydro- thostatic hypotension, nance dose according to clinical effect and aripiprazole tachycardia, QT inter- dose-dependent adverse reactions. (active).[47] val prolonged (risk for torsade de pointes)[1, 3]

20 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Chlorpro- Hi Hydroxyla- 1 30 95 22 32 36.1 0.67 Risk of extrapyramidal reac- Studies: Changes in EEG associated with mazine tion (major hepatic tions (acute dyskine- drowsiness and increased sensitivity in pa- pathway, encephalo- sia, akathisia, tardive tients with liver cirrhosis, particularly in pa- catalyzed pathy in dyskinesia, pseu- tients with previous history of encephalopa- mainly by patients doparkinsonism, thy.[49, 50] Should be avoided in patients with CYP 2D6 with liver dystonia), seizures, liver cirrhosis due to the risk of hepatic en- and partially cirrhosis.[49] galactorrhoea, cephalopathy.[49] Product information: Con- by CYP Sporadic: amenorrhea, gynae- traindicated in patients with cholestatic liver 1A2), N- cholestatic comastia, decreased injury. Personal recommendation: According demethyla- liver in- libido and sexual func- to pharmacokinetic data, start with 25-50% tion, N- jury.[4] tion, anticholinergic of normal initial dose. Adjust maintenance oxidation, effects (dry mouth, dose according to dose-dependent adverse deamina- blurred vision, urinary effects. tion, sulfoxi- retention, constipa- dation,[2, 48] tion), weight gain, partial bil- orthostatic hypoten- iary excre- sion, prolongation of tion.[1] QT interval (risk for torsade de pointes)[1, 2] Chlor- Hi Sulfoxidatio 0.95 12 99 15.5 12 72 >0.9 Sporadic: drowsiness, dizziness, Studies: No clinical studies available in pa- prothixene n, N- cholestatic extrapyramidal reac- tients with liver disease. Product information: demethylati liver in- tions (acute dyskine- Caution in patients with severe liver disease. on, jury.[4] sia, akathisia, tardive Dose adjustment recommended (no specifi- hydroxylatio dyskinesia, dystonia, cation). Personal recommendation: Accord- n, N- pseudoparkinsonism), ing to pharmacokinetic data, start with lowest oxidation.[1] seizures, galactor- possible dose (5mg). Adjust maintenance rhoea, amenorrhea, dose according to dose-dependent adverse gynaecomastia, de- reactions. creased libido, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation), weight gain, hypotension, arrhythmia[1, 2, 8]

21 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Clothiapine Nk Demethyla- 0.9 7.1 Sporadic: sedation, agitation, Studies: No clinical studies available in pation, oxida- elevated confusion, extrapyra- tients with liver disease. Product information: tion to N- aminotrans- midal symptoms In patients with liver insufficiency treatment oxide and ferase lev- (acute dystonia, acute should be started with lower doses and up- S-oxide els.[3] dyskinesia, akathisia, titrated slowly. Personal recommendation: derivatives, parkinsonism, tardive Clothiapine is extensively metabolized in the glucuronida- dyskinesia), hypoten- liver. According to missing pharmacokinetic tion.[1, 3, 51] sion, anticholinergic data, the drug should not be used in patients effects (blurred vision, with liver disease. dry mouth).[1] Clozapine Me N- 1 16 95 5 55 25.6 0.47 Rare: cho- drowsiness, dizziness, Studies: No clinical studies available in pa- demethyla- lestatic headache, anticho- tients with liver disease. According to studies tion to ac- and/or linergic effects (dry in rats expression of hepatic microsomal tive metabo- hepatocel- mouth, blurred vision, CYP 1A, 2E1, 2C11 and 3A decreased in lite N- lular liver urinary retention, con- steatosis.[53] Formation of N- desmethyl- injury.[4] stipation), extrapyra- desmethylclozapine and clozapine N-oxide clozapine midal reactions (e.g. decreased in microsomal fractions from stea- (CYP 1A2 akathisia, rigor, totic rat liver.[53] Product information: Clozap- and CYP tremor, tardive dyski- ine is contraindicated in patients with severe 3A4),[52] N- nesia), dysphagia, liver insufficiency. Reduction of initial dose [2] oxidation. seizures, transient andrecommendation: slow up-titration recommended in pa- temperature elevation, tients with liver disease (no specification) as weight gain, diabetes well as monitoring of liver function. Personal mellitus, tachycardia, According to kinetic data orthostatic hypoten- and product information, treatment should be sion, arrhythmia, res- started with 50% of normal initial dose. Ad- piratory depression[1, 2, just maintenance dose according to dose- 8] dependent adverse reactions and monitor liver function.

22 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Flupentixol Me Sulfoxida- 1 35 99 14 40 17.4 0.32 Occasion- drowsiness, dizziness, Studies: No clinical studies available in pation, N- ally: jaun- extrapyramidal reac- tients with liver disease. Product information: dealkylation, dice.[1] tions (akathisia, acute Cautionsonal recommendation: in patients with severe liver disease. glucuronida- dyskinesia, tardive Careful dosing due to possible accumulation tion, biliary dyskinesia, dystonia, in patients with impaired liver function. Per- excretion, pseudoparkinsonism), According to the entero- seizures, galactor- pharmacokinetic data, treatment should be hepatic rhoea, amenorrhea, started with 50% of a normal initial dose. circulation.[2] gynaecomastia, de- Adjust maintenance dose according to dose- creased libido, anti- dependent adverse reactions. cholinergic effects (dry mouth, blurred vision, urinary retention, constipation), weight gain, orthostatic hypotension, arrhythmia[1, 2, 8] Fluphenazin Hi Hydroxyla- 1 16.4 90 25 2.7 42 0.78 Rare: cho- extrapyramidal reac- Studies: No clinical studies available in pa- e tion, glu- (p.o.) lestatic liver tions (akathisia, acute tients with liver disease. Product information: curonida- injury.[4] dyskinesia, tardive In Switzerland only slow-release preparation tion, sulfoxi- dyskinesia, dystonia, for intramuscular injection available. Dose dation, de- pseudoparkinsonism), adjustment recommended in patients with methyla- seizures, galactor- impairedmendation: liver function. Contraindicated in tion,[6] biliary rhoea, amenorrhea, patients with liver injury. Personal recom- excretion, gynaecomastia, de- Only a slow-release preparation entero- creased libido and for intramuscular injection is available in hepatic sexual function, priap- Switzerland. In patients with liver disease circulation.[1] ism, anticholinergic alternatives should be used, since there are effects (dry mouth, no clinical studies. blurred vision, urinary retention, constipation), hypotension, arrhythmia[1]

23 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Haloperi- Me N- 1 18 92 17 60 38 0.7 Case re- extrapyramidal reac- Studies: No clinical studies available in pa- dol[54] Dealkylation port: cho- tions (acute dystonia, tients with liver disease. Product information: (CYP 3A4 lestatic liver acute dyskinesia, Caution in patients with liver disease. Dose and CYP injury.[55] akathisia, pseudopark- adjustment recommended (no specification). 2D6), reduc- insonism, tardive dy- Personal recommendation: According to the tion to ac- skinesia), insomnia, pharmacokinetic data, initial dose should be tive metabo- drowsiness, dizziness, reduced by 50%. Adjust maintenance dose lite (CYP anxiety, agitation, according to dose-dependent adverse reac- 3A4, CYP headache, galactor- tions. 2D6), glu- rhoea, menstrual dis- curonida- turbances, gynaeco- tion, 15% mastia, decreased excreted via libido, hypotension, the bile (no anticholinergic effects further (dry mouth, blurred specifica- vision, constipation), tion), un- tachycardia, arrhyth- dergoes mia, prolongation of entero- QT interval (risk for hepatic torsade de pointes), circulation.[2] seizure[1, 2, 8]

24 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Levome- Me Sulfoxida- 1 25 30 50 Rare: cho- drowsiness, ex- Studies:sonal recommendation: No clinical studies available in pa- promazine tion, glu- lestatic liver trapyramidal reactions tients with liver disease. Product information: (Methotrime curonida- injury.[1] (akathisia, acute dy- Caution in patients with hepatic failure. Per- prazine) tion, de- skinesia, tardive dy- According to phar- methyla- skinesia, pseudopark- macokinetic data, start with 50% of normal tion.[1] insonism, dystonia), initial dose and adjust maintenance dose seizures, galactor- according to dose-dependent adverse reac- rhoea, amenorrhea, tions. gynaecomastia, decreased libido and sexual function, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation), weight gain, arrhythmia, hypotension, prolongation of QT interval (risk for torsade de pointes)[1] Lithium Lo Renal elimi- 0.05 22 0 0.7 100 1.5 <0.01 Case re- hand tremor, polyuria, Studies:recommendation: No clinical studies available in pa- nation.[1] ports: as- thirst, nausea, hypo- tients with liver disease. Product information: cites, thyroidism, hypergly- No recommendations provided. Personal hyper- caemia, weight gain, Monitor creatinine clear- bilirubinae- diarrhoea, vomiting, ance and adjust maintenance dose accord- mia.[56, 57] drowsiness, muscular ingly. Monitor lithium serum concentrations. weakness, hallucinations, impaired memory, diabetes in- sipidus, sexual dysfunction, ECG changes, arrhythmia, seizures[1, 2]

25 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Olanzapine Me oxidation >0.85 33 93 14 60 26 0.4 Frequent: drowsiness, dizziness, Studies: No clinical studies available in pa- (CYP 1A2, asympto- headache, asthenia, tients with liver disease. Product information: CYP 2D6), matic hepa- weight gain, anticho- Since prolonged t1/2 expected in patients with glucuronida- tocellular linergic effects (dry liver disease, dose reduction is recom- tion.[1] injury.[58] mouth, constipation), mended (no specification). Because of tran- oedemas, galactor- sient increase in transaminases monitor liver rhoea, gynaecomas- function,tion: especially at the beginning of ther- tia, tachycardia, or- apy with olanzapine. Personal recommenda- thostatic hypotension, According to pharmacokinetic data, arrhythmia, prolonga- initial dose should be reduced by 50%. Ad- tion of QT interval (risk just maintenance dose according to dose- for torsade de dependent adverse reactions and monitor pointes), rare: ex- liver function. trapyramidal symptoms (akathisia, dystonia, pseudoparkinsonism, tardive dyskinesia)[1, 8] Penfluridol Lo N- nk 132 75 Rare: cho- extrapyramidal reac- Studies:sonal recommendation: No clinical studies available in pa- dealkylation, lestatic liver tions (akathisia, acute tients with liver disease. Product information: entero- injury.[1] dyskinesia, tardive Caution in patients with liver disease. Per- hepatic dyskinesia, dystonia, According to phar- circulation, pseudoparkinsonism), macokinetic data, avoid drug in patients with biliary ex- seizures, drowsiness, cholestatic liver injury, because of high bil- cretion dizziness, galactor- iary excretion. Start with a dose at the lower 80%.[1] rhoea, amenorrhea, end of normal range and adjust maintenance gynaecomastia, de- dose according to dose-dependent adverse creased libido, anti- reactions. cholinergic effects (dry mouth, blurred vision, urinary retention, constipation), weight gain, hypotension[1]

26 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Per- Hi Hydroxyla- 1 9.5 90 20 20 107 >0.9 Sporadic: drowsiness, ex- Studies:recommendation: No clinical studies available in pa- phenazine tion, de- cholestatic trapyramidal reactions tients with liver disease. Product information: methylation, liver in- (akathisia, acute dy- No recommendations provided. Personal sulfoxida- jury.[4] skinesia, dystonia, According to pharmacoki- tion, glu- tardive dyskinesia, netic data, start with the lowest possible curonida- pseudoparkinsonism), dose (2mg) and adjust maintenance dose tion.[2] Me- seizures, galactor- according to clinical effect and dose- tabolized rhoea, amenorrhea, dependent adverse reactions. primarily by gynaecomastia, de- CYP 2D6.[3] creased libido, sexual Entero- dysfunction, anticho- hepatic linergic effects (dry circulation.[1] mouth, blurred vision, urinary retention, constipation), weight gain, arrhythmia, hypotension, oedema[1, 2] Pipamper- Nk N- nk 6 Rare: liver extrapyramidal reac- Studies: No clinical studies available in pa- one dealkylation, dysfunc- tions (pseudoparkin- tients with liver disease. Product information: N-oxidation, tion, cho- sonism, dystonia, Patients with liver disease should be started and amide lestatic akathisia, acute dyski- on 10mg daily. Careful up-titration in incre- hydrolysis.[1, hepatitis.[1] nesia, tardive dyski- ments of 10mg daily according to the clinical 3] nesia), sedation, effect and dose-dependent adverse reac- drowsiness, insomnia, tions. Personal recommendation: Because of dizziness, headache, lack of data, no dose recommendations seizure, galactor- based on pharmacokinetic data possible. rhoea, menstrual dis- The drug should be avoided in patients with turbances, gynaeco- severe liver disease. mastia, anticholinergic effects (dry mouth, blurred vision, constipation), orthostatic hypotension, tachycardia, arrhythmia, prolongation of QT interval (risk for torsade de pointes)[1]

27 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Promazine Hi Hydroxyla- 1 15 92 16[60] Phenothi- drowsiness, sedation, Studies: In patients with hepatic cirrhosis tion (fol- (var) azines may extrapyramidal reac- (Child-Pugh class A and B), total and free lowed by cause in- tions (akathisia, acute plasma clearance decreased by 76% and conjuga- trahepatic dyskinesia, dystonia, 89%, t1/2 was 2 times and AUC 2.9 times tion), N- cholesta- tardive dyskinesia, higher compared with healthy subjects.[61] oxidation, sis[2] pseudoparkinsonism), Unbound fraction was also significantly N- confusion, seizures, higher (35.5% vs 10.4%). However, no demethyla- galactorrhoea, change in pharmacokinetic parameters dur- tion (CYP amenorrhea, gynae- ing acute phase of viral hepatitis B, but more 1A2, CYP comastia, decreased pharmacodynamic adverse effects observed 2C19), sul- libido and sexual func- (sedation, postural hypotension, dizzi- foxidation tion, anticholinergic ness).[62] Dosage should be adjusted in the (CYP 1A2, effects (dry mouth, liver cirrhosis patients (no specific dosage CYP 3A4).[2, blurred vision, urinary recommendation).[61] Product information: 59] retention, constipa- Caution in patients with liver disease.[1] Use tion), weight gain, not recommended in patients with liver dis- hypotension, tachy- easemendation: because phenothiazines may cause cardia, arrhythmia, intrahepatic cholestasis.[2] Personal recom- prolongation of QT According to the pharmacoki- interval (risk for tor- netic parameters, start with 25% of normal sade de pointes)[1, 2] initial dose. Adjust dosage according to dose-dependent adverse reactions.

28 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Quetiapine Hi Dealkyla- 0.95 6 83 10 9 79.8 >0.9 Rare: jaun- drowsiness, dizziness, Studies: Compared with healthy controls tion, hy- dice, tran- headache, asthenia, clearance decreased by 25% in patients with droxylation sient and anticholinergic effects liver cirrhosis, AUC and Cmax increased by [65] (CYP 3A4, reversible (dry mouth, constipa- 40% and t1/2 prolonged by 77%. The au- CYP 2D6 elevations tion), oedema, weight thors concluded that patients with hepatic [minor]), in serum gain, tachycardia, liver cirrhosis may be given 25mg quetiapine sulfoxida- transami- orthostatic hypoten- astion: starting dose and dose escalation should tion, glu- nase (pri- sion, syncope, prolon- be conducted with caution. Product informa- curonida- marily gation of QT interval Recommendations based on the study tion.[63] ALT).[1, 3] (risk for torsade de from Thyrum PT et al.[65] conducted by Astra Case re- pointes), rare: ex- Zeneca. Start with 25mg quetiapine on the port: sub- trapyramidal symp- first day. Up-titrate carefully in increments of fulminant toms (acute dystonia, 25-50mg/d to an effective dose, depending liver fail- tardive dyskinesia)[1, 8] on clinical response and dose-dependent [64] tion: ure. adverse reactions. Personal recommenda- According to pharmacokinetic data and clinical study, start with 25mg and up-titrate carefully according to clinical effect and dose-dependent adverse reactions.

29 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Risperidone Me 9- 1 3.2 88 1.5 66 22.7 0.42 Rare: in- insomnia, drowsiness, Studies: No change in single-dose kinetics of hydroxyla- creased dizziness, anxiety, risperidone and the active moiety (risperi- tion (by liver en- agitation, headache, done and 9-hydroxyrisperidone) in patients CYP 2D6) zymes.[1] extrapyramidal reac- with liver cirrhosis compared with healthy to active Case re- tions (e.g. pseu- subjects.[67] Product information: PB of metabolite port: cho- doparkinsonism, acute risperidone may be diminished in patients 9- lestatic liver dystonia, akathisia, with liver disease. Risperidone plasma con- hydroxy- injury.[66] tardive dyskinesia), centration within the normal range in patients risperidone, galactorrhoea, men- with liver disease, but mean free fraction of N- strual disturbances, risperidone increased by 35%. Reduce initial dealkyla- gynaecomastia, de- and maintenance dose by 50%. Only slow tion.[1] creased libido, priap- up-titration of the dose in patients with liver ism, weight gain, anti- disease. Personal recommendation: Accord- cholinergic effects (dry ing to pharmacokinetic data, start with 50% mouth, blurred vision, of the initial dose and adjust maintenance constipation), hy- dose according to dose-dependent adverse potension, tachycar- reactions. dia, arrhythmia, prolongation of QT interval (risk for torsade de pointes)[1, 2] Sertindole Lo Oxidation of 1 72 99.5 20 74 14 0.26 drowsiness, somno- Studies: No clinical studies available in pa- imidazolidi- lence, dizziness, tients with liver disease. Product information: non ring to headache, weight Clearance decreased by 50% in patients dehydros- gain, anticholinergic with liver failure. Start with low initial dose ertindole, N- effects (dry mouth, andrecommendation: up-titrate carefully in patients with mild dealkylation constipation, blurred to moderate liver failure. Contraindicated in to norsertin- vision), oedemas, patients with severe liver failure. Personal dole (both decreased volume of According to the pharma- inactive) by ejaculation, tachycar- cokinetic data and product information start CYP 2D6 dia, orthostatic hy- with normal initial dose (4mg/d). Adjust main- and CYP potension, arrhythmia, tenance dose according to dose-dependent 3A4.[1, 47] prolongation of QT adverse reactions. interval (risk for torsade de pointes), rare: extrapyramidal symptoms (e.g. tardive dyskinesia)[1]

30 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Sulpiride Lo Renal elimi- 0.3 8 40 1.5 30 7.6 0.04 Rare: cho- extrapyramidal reac- Studies:sonal recommendation: No clinical studies available in pa- nation.[1] lestatic liver tions (pseudoparkin- tients with liver disease. Product information: injury.[4] sonism, acute dyski- No dose recommendations provided. Per- nesia, acute dystonia, Because of renal akathisia, tardive dy- elimination of sulpiride, no dose adjustment skinesia), drowsiness, may be needed due to hepatic impairment. somnolence, insom- Monitor creatinine clearance and adjust nia, dizziness, anxiety, maintenance dose accordingly. motor agitation, headache, seizures, weight gain, galactorrhoea, amenorrhea, gynaecomastia, decreased libido, anticholinergic effects (dry mouth, blurred vision, urinary retention), hypotension, arrhythmia, prolongation of QT interval (risk for torsade de pointes)[1, 2] Tiapride Lo Renal elimi- 0.25 3 0 1.4 80 sedation, drowsiness, Studies:recommendation: No clinical studies available in pa- nation.[1] extrapyramidal symp- tients with liver disease. Product information: toms (acute dyskine- No recommendations provided. Personal sia, dystonia, Monitor creatinine clear- akathisia, tardive dy- ance and adjust maintenance dose accord- skinesia, pseudopark- ingly. insonism), insomnia, agitation, dizziness, headache, orthostatic hypotension, galactorrhoea, gynaecomastia, amenorrhea, sexual dysfunction[1]

31 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Zuclopen- Me Metabolism 1 20 99 20 50 51.6 0.96 Frequency somnolence, drowsi- Studies: No clinical studies available in pa- thixol via CYP unknown: ness, dizziness, ex- tients with liver disease. Product information: 2D6. Sul- Transient trapyramidal reactions Caution in patients with liver disease. Rec- foxidation, elevations (akathisia, acute dy- ommendationdation: for dosage reduction (no spe- N- in serum skinesia, dystonia, cific recommendation). Personal recommen- dealkylation, transami- tardive dyskinesia, According to pharmacokinetic data, glucuronida- nases.[3] pseudoparkinsonism), start with 50% of normal dose and adjust tion,[1] en- seizures, galactor- maintenance dose according to dose- terohepatic rhoea, amenorrhea, dependent adverse reactions. circulation.[2] gynaecomastia, decreased libido, anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation), weight gain, hypotension, tachycardia[1, 2] Anxiolytics, hypnotics, sedatives [68] Alprazolam Lo CYP3A, 0.8 12 70 1.1 92 4.6 0.07 Risk of drowsiness, dizziness, Studies: T1/2 increased by 50% and clear- alpha-OH- hepatic confusion, memory ance of the drug reduced by 50% in patients alprazolam encephalo- impairment, ataxia, with alcoholic liver cirrhosis. Changes in t1/2 (active me- pathy in muscle weakness, and clearance indicated that the metabolism tabolite).[2] patients blurred vision, respira- of the drug is slowed in patients with alco- with liver tory depression[1, 2, 8] holic cirrhosis.[69] Daily dose should be re- cirrhosis.[2] duced by 50% in patients with alcoholic liver Rare: cho- cirrhosis.[69] Product information: Recom- lestatic liver mended initial dose in patients with liver injury.[4] disease is 0.25mg given 2 or 3 times daily or 0.5mg once daily as extended-release tab- let.[8] Dosage may be gradually increased according to dose-dependent adverse reactions.[8] Personal recommendation: Accord- ing to pharmacokinetic data and product information start with 0.25mg given 2 or 3 times daily or 0.5mg once daily and adjust dosage according to dose-dependent adverse reactions. Lorazepam, oxazepam, and temazepam are the benzodiazepines of

32 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects choice for patients with liver disease. Bromaze- Lo Hydroxyla- 1 16 70 0.7 60 2.5 0.05 fatigue, drowsiness, Studies: No clinical studies available in pa- pam tion to hy- confusion, dizziness, tients with liver disease. Product information: droxybro- ataxia, muscle weak- Bromazepamsonal recommendation: is contraindicated in patients mazepam.[1] ness, respiratory de- with severe liver insufficiency, because of pression[1] the risk for hepatic encephalopathy. Per- According to pharmacokinetic data, maintenance dose may be reduced up to 50%. Adjust dose according to dose-dependent adverse reactions. Loraze- pam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

33 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects [1] Buspirone Hi CYP 3A, 1 2.4 95 5 4 92.5 >0.9 drowsiness, dizziness, Studies: Cmax about 16 times higher in pa- oxidative headache, light- tients with liver cirrhosis than in controls.[70] dealkylation headedness, nausea, T1/2 in patients with cirrhosis about twice that to 1- vomiting, myosis, of normal subjects. At steady state, Cmax was pyrimidinyl paraesthesia, sleep- 9- and 12-fold higher in compensated (n=6) piperazine lessness, nervous- and decompensated (n=6) cirrhotics com- [1] (active), ness pared with controls (n=12), t1/2 was increased hydroxyla- by 169% and 204%, and AUC increased by tion, glu- 752% and 1773%.[71] Intensity and frequency curonida- of adverse effects were similar in cirrhotics tion.[2] and controls. No significant difference in pharmacokinetics of 2-pyrimidinyl piperazine between cirrhotic patients and controls. However, due to high intra- and inter-subject variability of the plasma buspirone concen- trationsonal recommendation:data, dosing recommendations could not be made.[71] Product information: Contra- indicated in patients with liver disease. Per- According to pharmacokinetic data, start with lowest possible dose (5mg) due to variable bioavailability in patients with porto-systemic shunts. Adjust maintenance dose according to dose- dependent adverse reactions. Dose interval may be reduced from 3 times to 1-2 times daily.

34 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Chloral hy- Nk Alcohol 0.95 8 40 0.6 drowsiness, head- Studies: No clinical studies available in pa- drate dehydro- ache, lethargy, confu- tients with liver disease. Product information: genase to sion, ataxia, irritation Contraindicated in patients with severe liver trichloro- of the stomach, flatu- injury. Personal recommendation: Because ethanol lence, nausea, diar- of lack of data, no dose recommendation can (active).[2] rhoea, respiratory be made. Pharma- depression, arrhyth- cokinetic mia, hypotension[1, 2] data refer to trichloretha- nol. Trichlo- rethanol is mainly glu- curonidated and excreted biliary as uro- chloralic acid.[2]

35 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Chlordi- Lo N- 1 15 95 0.35 >86 1.7 0.03 Case re- somnolence, dizzi- Studies: T1/2 increased 2.4-3.5-fold, clear- azepoxide demethyla- ports: jaun- ness, drowsiness, ance reduced by 50-66% and Vd increased tion, 4- dice, eleva- confusion, ataxia, by 33-63% in patients with cirrhosis, alco- hydroxyla- tion of liver muscle weakness, holic hepatitis (9 of 15 patients with cirrhosis) tion, deami- enzymes, nausea, constipation, or acute hepatitis compared with healthy nation, glu- hepatocel- respiratory depres- controls.[72-74] Clearance of unbound drug curonida- lular liver sion[1, 2, 8] reduced by 60% in cirrhotics compared with tion, hy- injury, cho- controls, only minimal change in PB.[73] Op- drolysis to lestatic liver posed results concerning correlation be- [3] an opened injury, tweeninformation: albumin levels and clearance ob- lactam.[2] may pre- served.[72, 74] Elimination of desmethylchlor- cipitate diazepoxide slowed in cirrhotics.[74] Product hepatic tion: Contraindicated in patients with encephalo- severe liver disease. Personal recommenda- pathy in Start with initial dose in the lower range patients of normal. Reduce maintenance dose by with liver 50% or reduce administration to 1-2 times disease.[72] daily. Adjust maintenance dose according to dose-dependent adverse reactions. Accumu- lation of active metabolite may occur (longer t1/2 than parent compound). Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

36 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Clobazam Lo N- 1 20 90 1 >86 2 0.04 fatigue, drowsiness, Studies: T1/2 was significantly longer in pa- dealkylation confusion, dizziness, tients with liver cirrhosis and viral hepatitis to active ataxia, muscle weak- compared with normal subjects (51h and metabolite, ness, respiratory de- 47h, respectively, vs 22h), Cmax significantly hydroxyla- pression[1, 2] lower (240ng/ml and 239ng/ml vs 350ng/ml), [2] tion. Vd significantly higher (178l and 173l vs 81l), whereas total plasma clearance was not [75] different. While Cmax and t1/2 of norcloba- zam were similar between patients and con- tion: trols, tmax was significantly longer in patients withrecommendation: cirrhosis and hepatitis. Product informa- Maintenance dose should be reduced by 50% (normal dose: 20-30mg/d). Personal According to pharmacokinetic data, clinical studies und product information, reduce maintenance dose by 50% and adjust dosage according to dose- dependent adverse reactions. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

37 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Clomethia- Hi Metabolized 0.95 6 65 9 10 100 >0.9 Elevation of tingling sensation in Studies: Clearance decreased by 30% and zole via CYP transami- the nose, sneezing, bioavailability 10 times higher in patients with 2A6, CYP nases. nasal congestion, advanced alcoholic liver cirrhosis compared 3A4/5, CYP Rare: jaun- conjunctival irritation, with healthy subjects.[76] Dose reduction rec- 2B6, CYP dice, cho- hypotension, tachy- ommended (no specification).[76] After con- 1A1, CYP lestatic cardia, cardiac arrest, tinuous infusion of clomethiazole, systemic [1] [1] 2C19. hepatitis. sedation, respiratory clearance decreased by 50% and t1/2 pro- depression[1, 2] longed by 90% in patients with cirrhosis [77] Child-Pughinformation: class B and C. No significant difference between subjects with mild liver impairment and healthy controls. Product Avoid in patients with severe liver disease, because sedation may mask the beginning of hepatic coma. Clomethia- zole should not be given to alcoholics with liver cirrhosis, because fatal respiratory de- pressiontion: may result in combination with alcohol consumption. Personal recommenda- Oral administration should be avoided in patients with liver cirrhosis since bioavailability is unpredictable. Intravenous therapy with 25-50% of normal dose and adjustment according to dose-dependent adverse reactions. Lorazepam, oxazepam and temazepam are better alternatives.

38 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Clorazepate Lo Clorazepate 1 80 98 1.3 91 0.71 0.01 Risk of fatigue, drowsiness, Studies: No clinical studies available in pa- is a pro- hepatic confusion, dizziness, tients with liver disease. Product information: drug: active encephalo- impairment of mem- Smallestommendation: effective initial dose recommended form is N- pathy in ory, ataxia, asthenia, for patients with liver disease. Personal rec- desmethyldi cirrhotic muscle weakness, According to pharmacokinetic azepam. N- patients.[1] blurred vision, diplo- data, start with initial dose in the lower range desmethyldi pia, slurred speech, of normal and adjust maintenance dose ac- azepam is decreased libido, res- cording to dose-dependent adverse reac- hydroxy- piratory depression[1, 2] tions. Lorazepam, oxazepam, and temaze- lated to pam are the benzodiazepines of choice for oxazepam patients with liver disease. (active) by CYP 3A4 and 2C19.[1, 2] The pharmacokinetic data refer to the active form.

39 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Diazepam Lo N- 1 42 98 1.5 100 1.6 0.03 Rare: cho- drowsiness, fatigue, Studies: T1/2 of diazepam 2-fold higher in demethyla- lestatic liver ataxia, muscle weak- cirrhotics compared with controls,[78-80] total tion (CYP injury, ness, confusion, dizzi- clearance reduced by 48%, Vd increased by 2C19), hy- jaundice, ness, impairment of 54% and PB decreased by 3%.[79] Significant droxylation elevations memory, diplopia, increase in t1/2 by 113% and decrease in (CYP 3A4), of transa- blurred vision, dy- clearance by 58% of desmethyldiazepam.[80] glucuronida- minases.[1, sarthria, hypotension, Despite similar concentrations differences in tion; N- 4] incontinence, urinary EEG observed in cirrhotics suggesting desmethyldi retention, constipation, higher cerebral sensitivity.[81] Patients with azepam, changes in libido, liver disease required 66% of the dose until oxazepam slurred speech, respi- nystagmus, dysarthria and sedation devel- and te- ratory depression[1, 2, 8] oped compared with controls.[81] Patients mazepam with cirrhosis and hepatitis are at risk for are active accumulation an deeper sedation after multi- metabo- ple dosing.[82] Dose reduction by 50% rec- lites.[2] ommended.[81] Product information: Contra- indicated in patients with severe liver disease. Personal recommendation: According to kinetic data and clinical studies reduce maintenance dose by 50%. Adjust dosage according to dose-dependent adverse effects. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice.

40 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Diphenhy- Me N- 0.98 8.5 90 4.5 50 26 0.47 sedation, dizziness, Studies: Nine patients with ethanol-induced dramine demethyla- tinnitus, ataxia, blurred chronic liver disease and eight healthy sub- tion[2] by vision, diplopia, dry jects were administered intravenous diphen- CYP 2D6 mouth, headache, hydramine 0.8 mg/kg i.v. as a single sedative [84] and to a nausea, vomiting, dose. T1/2 increased by 163% and PB lesser ex- constipation, urinary decreased by 15% in patients with alcoholic tent by CYP retention, tachycardia, liver cirrhosis. No apparent increase in cere- 1A2, 2C9 arrhythmia, convul- bral sensitivity was observed in patients with and 2C19[83] sions[1, 2] liver cirrhosis. Multiple doses of diphenhy- draminetion: in patients with chronic liver disease have not been evaluated. Product informa- Caution in patients with liver disease. Personal recommendation: Based on the pharmacokinetic data, start with 50% of normal initial dose. Adjust maintenance dose according to dose-dependent adverse effects. Doxylamine Nk N- nk 10 2.5 13.7 sedation, dizziness, Studies:recommendation: No clinical studies available in pa- dealkylation, blurred vision, dry tients with liver disease. Product information: N-acetyl mouth, headache, No recommendations provided. Personal conjuga- nausea, vomiting, Because of lack of phar- tion.[85] constipation, urinary macokinetic data, no dose recommendation retention, tachycar- can be made. dia[1]

41 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Flunitraze- Lo N- 1 29 78 3 85 7.8 0.14 Risk of drowsiness, dizziness, Studies: Plasma levels and pharmacokinetic pam demethyla- hepatic confusion, nightmares, parameters (oral clearance, t1/2) not altered tion to ac- encephalo- muscle weakness, in patients with liver cirrhosis or hepatitis tive metabo- pathy in ataxia, respiratory compared with healthy volunteers.[87] How- lite (CYP patients depression[1] ever, plasma levels of N-desmethyl fluni- 2C19, CYP with liver trazepam were lower in patients than in 3A4), hy- cirrhosis.[2] healthy subjects. Product information: Fluni- droxylation trazepammendation: is contraindicated in patients with (CYP 3A4), severe liver insufficiency. Personal recom- reduction of According to pharmacokinetic the 7-nitro data, doses in the lower range of normal substitu- (0.5mg/d) should be used and adjusted ac- ents.[86] cording to dose-dependent adverse reactions. Use is discouraged, however, due to long t1/2. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease. Flurazepam Hi N- 1 2 95 3.4 30 Rare: cho- drowsiness, dizziness, Studies: No clinical studies available in pa- desalkyla- lestatic liver lightheadedness, tientssonal withrecommendation: liver disease. Product information: tion and injury.[4] ataxia, blurred vision, Flurazepam should be used with caution in hydroxyla- slurred speech, respi- patients with impaired hepatic function. Per- tion to ac- ratory depression[1, 2, 8] Flurazepam is not tive metabo- an ideal hypnotic in patients with liver dis- lites hy- ease. Lorazepam, oxazepam, and temaze- droxyethylfl pam are the benzodiazepines of choice for urazepam patients with liver disease. and N- desalkylflu- razepam.[2]

42 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Hydroxyzine Hi Hepatic 1 20 16 41.1 0.76 Rare: he- anticholinergic effects Studies: T1/2 was 36.6h, clearance 36.3 L/h metabolism patic or (dry mouth, confusion, and Vd 23 L/kg in patients with primary biliary [88] to cetirizine cholestatic constipation, blurred cirrhosis.information: T1/2 of cetirizine was 25h. In- (active me- jaundice.[1] vision, urinary reten- crease normal dosage interval of 2-3 times tabolite),[88] tion, tachycardia), daily to once per 24 hours or less.[88] Product 70% of the drowsiness, ataxia, In patients with liver cirrhosis, dose elimi- hypotension, seda- clearance was reduced by about 66%. T1/2 nated by tion[1] was increased to 37h and serum concentra- biliary ex- tions of cetirizine were higher compared with cretion.[1] healthy individuals. Dosage reduction is indicated in patients with moderate impaired ommendation: liver function. Contraindicated in patients with severe liver insufficiency. Personal rec- According to the pharmacokinetic data, start with 50% of normal initial dose (12.5mg). Adjust maintenance dose according to dose-dependent adverse reactions. Ketazolam Nk N-demethy- 1 2 93 drowsiness, dizziness, Studies: No clinical studies available in pa- lation to N- lethargy, ataxia, con- tients with liver disease. Product information: desmethyldi fusion, blurred vision, Ketazolam is extensively metabolized follow- azepam and respiratory depres- ing oral administration and dosing adjust- [1, 2] N-des- sion mentsrecommendation: may be indicated in patients with liver methylketa- disease.[3] Adjust dose according to dose- zolam (both dependent adverse reactions.[1] Personal active);[2] Because of lack of data no low concen- dose recommendation can be made. tration of Lorazepam, oxazepam, and temazepam are diazepam; the benzodiazepines of choice for patients oxazepam with liver disease. is the major urinary metabolite, excreted mainly glucuroni- dated.[2]

43 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Lorazepam Lo Glucuroni- 1 14 90 1.3 93 4.6 0.09 frequency sedation, drowsiness, Studies: T1/2 increased by 90% and Vd in- dation[2] unknown: headache, dizziness, creased by 57%, while PB decreased by 5% increased confusion, asthenia, in patients with alcoholic liver cirrhosis com- bilirubin, depression, blurred pared with healthy controls.[89] No changes in jaundice, vision, diplopia, systemic clearance of total and unbound elevation of slurred speech, ataxia, drug observed. Acute viral hepatitis had no transami- muscle weakness, effect on the disposition kinetics of loraze- nases or respiratory depres- pam.[89] Product information: No changes in AP, risk of sion[1, 2] the kinetics in patients with hepatitis and hepatic alcoholic liver cirrhosis observed. Dose ad- encephalo- justment recommended, 50% of normal dose pathy.[1] (normal dose: 2mg/d) in patients with liver cirrhosis, monitor patients well. Avoid par- enteral application in patients with liver failure. Personal recommendation: Start with a dosage in the lower range of normal and adjust maintenance dose according to dose- dependent adverse reactions. Lormetaze- Lo Glucuroni- 0.85 10 85 4.6 90 Very rare: drowsiness, confu- Studies: Minor changes in the kinetics of pam dation (ma- cholestatic sion, dizziness, mus- lormetazepam in patient with liver cirrho- jor), N- liver dis- cle weakness, ataxia, sis.[91] Dose adjustment not necessary in demethyla- ease.[6] respiratory depres- singletion: oral and multiple dose therapy in pation (mi- sion[1, 6] tients with liver cirrhosis.[91] Product informa- nor).[1] Par- Caution in patients with severe hepatic tial biliary dysfunction. Personal recommendation: Ac- excretion cording to the pharmacokinetic data, use 0.3-2.8%.[90] maintenance dose in the lower range of normal (0.5mg/d) and adjust dosage according to dose-dependent adverse reactions. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

44 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Mepro- Lo Hydroxyla- 0.9 10 20 0.6 3 0.05 Rare: hepa- drowsiness, ataxia, Studies: No clinical studies available in pa- bamate tion[1] tocellular dizziness, lethargy, tients with liver disease. Product information: [4] injury, paraesthesia, muscle Increased t1/2 (24h) in patients with liver cir- cholestatic weakness, blurred rhosis or chronic hepatitis. However, no spe- jaundice, vision, tachycardia, cific dosage recommendations are available. induction of palpitations, hypoten- Personal recommendation: According to the acute in- sion, respiratory de- pharmacokinetic data, use maintenance termittent pression[1] dose in the lower range of normal and adjust porphyria.[1] dosage according to dose-dependent adverse reactions. Methaqualo Lo Hydroxyla- 0.9 35 80 6 75 8 0.13 drowsiness, dizziness, Studies: No clinical studies available in pa- ne tion, biliary dry mouth, sweating, tients with liver disease. Product information: excretion, gastrointestinal distur- Contraindicated in patients with liver insuffi- entero- bances, tremor, sei- ciency. Personal recommendation: Accord- hepatic zures[1] ing to pharmacokinetic data, start with dos- circulation.[1] age in the lower range of normal and adjust dosage according to dose-dependent adverse reactions.

45 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Midazolam Me CYP 3A4, 1 2.5 96 1 44 24 0.44 drowsiness, confu- Studies: Clearance was reduced by 41-58% hydroxyla- sion, dizziness, and t1/2 increased up to 165% (range 24- tion to ac- blurred speech, 165%) in cirrhotics compared with healthy [92-95] [95] tive alpha- ataxia, muscle weak- subjects. Vd not significantly altered. hydroxymi- ness, respiratory de- Bioavailability may increase from 30% to dazolam.[1, 2] pression[1, 2] 76% in patients with portosystemic shunts.[92] Free fraction was 4.9% in cirrhotics and 1.9% in controls (p<0.01),[95] Pentikainen et al.[94] reported no change in PB. Overall increased pharmacological effects with greater sedationtion: were observed.[93, 95] Dose adjustment is recommended.[94] Product informa- ommendation: Midazolam is contraindicated in patients with severe liver insufficiency. Personal rec- According to the pharmacokinetic data, oral treatment should be started with 50% of normal dose. Adjust maintenance dosage according to dose-dependent adverse reactions. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease. Nitrazepam Lo Reduction 1 30 85 2 78 4 0.07 Case re- drowsiness, light- Studies: No significant differences in t1/2, of the nitro port: cho- headedness, dizzi- total clearance and Vd in patients with liver group fol- lestatic liver ness, confusion, seda- cirrhosis. However, free drug clearance de- lowed by injury.[4] tion, ataxia, slurred creased significantly by 32% and free frac- acetyla- speech, muscle tion increased by 35% in patients with liver tion.[2] weakness, respiratory cirrhosis.[96] Dose adjustment recommended depression[1, 2] in patients with liver cirrhosis (no quantifica- tion).[96] Product information: Contraindicated in patients with severe liver insufficiency. Personal recommendation: According to the pharmacokinetic data, doses in the lower range of normal should be used. Adjust maintenance dose according to dose- dependent adverse reactions (potential dose reduction up to 50%). Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

46 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Oxazepam Lo Glucuroni- 1 7 98 1 90 8 0.15 frequency sedation, drowsiness, Studies: Kinetics not changed in patients dation[2] unknown: headache, dizziness, with liver cirrhosis or acute viral hepatitis.[74, jaundice, depression, ataxia, 97] Dose adjustment not necessary for pa- bilirubin muscle weakness, tients with liver cirrhosis or hepatitis (excel- increased, asthenia, respiratory lent sedative for patients with liver dis- increase of depression[1, 2] ease).[97] Product information: Monitor pa- transami- tients with liver insufficiency and adjust dose nases or according to clinical effect and dose- AP,[1] risk of dependent adverse reactions. Contraindi- hepatic cated in patients with severe liver insuffi- encephalo- ciency. Personal recommendation: Accord- pathy.[1, 2] ing to pharmacokinetic data and clinical studies, start with dosage in the lower range of normal and adjust maintenance dose according to dose-dependent adverse effects. Praze- Lo Prazepam is 1 80 97 2 1.2 0.02 drowsiness, fatigue, Studies: No clinical studies available in pa- pam[98] a prodrug. muscle weakness, tients with liver disease. Product information: Dealkylation ataxia, confusion, Contraindicated in patients with severe liver to N- dizziness, impairment disease. Personal recommendation: Accord- desmethyldi of memory, diplopia, ing to pharmacokinetic data, start with initial azepam blurred vision, dy- dose in the lower range of normal and adjust (active).[1] sarthria, changes in maintenance dose according to dose- N- libido, respiratory de- dependent adverse effects. Lorazepam, desmethyldi pression[1] oxazepam, and temazepam are the benzo- azepam is diazepines of choice for patients with liver hydroxy- disease. lated to oxazepam. Pharma- cokinetic data refer to N- desmethyldi azepam.

47 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Pro- Hi Sulfoxida- 1 12 85 14 25[60] 68 >0.9 jaundice[3] sedation, somnolence, Studies: No clinical studies available in pa- methazine tion, N- dizziness, confusion, tients with liver disease. Product information: dealkylation disorientation, ex- Caution in patients with liver impairment.[8] (CYP 2D6). trapyramidal symp- Personal recommendation: In Switzerland Major route toms (if used at neuro- only a combination of promethazine with of elimina- leptic doses), ataxia, carbocisteine as expectorant is available. tion via bil- dysarthria, fatigue, Promethazine is contained at lower dose iary excre- diplopia, seizures, compared with a monosubstance preparation.[2] hypotension, tachy- tion available in the USA, therefore no rec- cardia, respiratory ommendation for patients with liver disease depression (especially are made. children), anticholinergic effects (blurred vision, dry mouth)[1, 2] Temazepam Lo Glucuroni- 1 9 96 1.4 80 4 0.07 Risk of drowsiness, dizziness, Studies: No significant changes of the phar- dation, de- hepatic confusion, prolonged macokinetics in patients with alcoholic liver methylation encephalo- reaction time, muscle cirrhosis.[99] Free drug clearance was only to oxaze- pathy in weakness, ataxia, modestly reduced. Slower absorption and pam (<5%), patients respiratory depres- delayed hypnotic activity possible in patients entero- with severe sion[1, 2] with liver cirrhosis, but rate of elimination and hepatic liver insuffi- extent of accumulation not altered compared circulation ciency.[1] withuct information:healthy persons.[100] No significant dif- (shown in ference in clearance of total and unbound rats).[1, 2] temazepam or free fraction observed. Prod- Caution in patients with severe liver insufficiency, because of the risk for hepatic encephalopathy. No significant change in pharmacokinetic parameters in patients with liver cirrhosis. Patients with impaired liver function need regular monitoring. Adjust dosage according to the patients reaction and consider dosage reduction. Personal recommendation: According to clinical studies and pharmacokinetic data, start with a dose in the lower range of normal (10mg/d) and adjust dosage according to dose-dependent adverse reactions.

48 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Triazolam Me Hydroxyla- 1 3 80 1.6 53 31.5 0.58 Risk of sedation, drowsiness, Studies: Increased sedation in patients with tion (CYP hepatic dizziness, ataxia, ab- cirrhosis due to decreased free drug clear- 3A) to al- encephalo- normal coordination, ance by 38%, and hypersensitivity of the pha- pathy in blurred vision, respira- brain.[102] Free fraction was higher compared hydroxytria- patients tory depression[1] with controls (17% vs 14%; p<0.001). Similar zolam and with liver results shown by Kroboth et al.:[103] clear- 4- cirrhosis.[2] ance decreased by 25% in cirrhotics, while hydroxytria- Rare: cho- Cmax was not different compared with normal zolam with lestatic liver subjects after triazolam 0.25mg as night time subsequent injury.[4] sedative. Oral clearance was related to al- glucuronida- bumin concentration. No difference in kinet- tion.[2, 101] ics were found between patients with mild to moderate hepatic dysfunction and age- matched controls.[104] For night time sedation patients with severe liver dysfunction may receive 0.125mg triazolam as initial dose.[103] Product information: Caution in patients with liver disease. Personal recommendation: According to the pharmacokinetic data and data from clinical studies, start with lowest possible dose (0.125mg). Adjust dosage according to dose-dependent adverse reactions. Lorazepam, oxazepam, and temazepam are the benzodiazepines of choice for patients with liver disease.

49 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Zaleplon Hi Aldehyde 1 1 60 1.4 31 70 >0.9 somnolence, ataxia, Studies: No clinical studies available in pa- oxidase, drowsiness, asthenia, tients with liver disease. Product information: desalkyla- respiratory depres- Oral clearance reduced by 70% and 87% in tion by sion[1, 8] compensated and decompensated cirrhotic CYP3A4, patients, respectively, up to 4-fold increase followed by in Cmax and up to 7-fold increase in AUC in glucuronida- comparison with healthy subjects.[8] Contra- tion.[1] indicated in patients with liver insufficiency.[1] Personal recommendation: According to pharmacokinetic data and product information, start with lowest possible dose in patients with mild to moderate hepatic insufficiency (5mg). Adjust dosage according to dose-dependent adverse reactions. Zaleplon should be avoided in patients with severe hepatic impairment. Better alternatives are available: lorazepam, oxazepam and temazepam. Zolpidem Me Hydroxyla- 1 2 93 0.5 70 18.2 0.34 Rare: somnolence, dizzi- Studies: No clinical studies available in pation, oxida- hyper- ness, drowsiness, tients with liver disease. Product information: tion (by bilirubinae- hallucinations, night- Following a single 20mg oral dose, mean [2] [1] CYP3A4), mia. Case mares, asthenia, con- Cmax and AUC were 2-fold and 5-fold in- report [1, 2] partial bil- : fusion creased in patients with chronic hepatic in- iary excre- hepatocel- sufficiency compared with healthy subjects. [105] tion. lular and Mean t1/2 increased from 2.2h in normal to cholestatic 9.9h in cirrhotic patients.[8] Recommended (mixed) dose is 5mg/d in patients with liver insuffi- liver in- ciency.mendation:[1] Contraindicated in patients with jury.[106] severe liver insufficiency.[1] Personal recom- According to pharmacokinetic data and product information, start with 5mg/d and adjust maintenance dose according to dose-dependent adverse reactions.

50 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Zopiclone Lo N-oxidation 0.95 5 45 1.4 80 13.9 0.24 Very rare: dry mouth, somno- Studies: T1/2 prolonged from 3.5h to 8.5h in (CYP 3A4) increase in lence, dizziness, con- cirrhotics compared with healthy individu- [108] to N-oxid- liver en- fusion, hallucinations, als. Mean Cmax not significantly different, [1] [1, 2] zopiclone zymes. fatigue but tmax delayed by 2h (not statistically sig- (active in nificant). Response to zopiclone was de- animals), N- layed and possibly exaggerated in cirrhosis. demethyla- Delayed tmax (3.5h vs. 0.5h), higher AUC tion (CYP (43%), increased bioavailability (97% vs. 75- 2C8) to N- 80%) and prolonged t1/2 (8.4h vs. 5h) ob- desmethyl- served in patients with liver insufficiency zopiclone, compared with healthy subjects.[107] Reduc- decarboxy- tion of initial dose from 7.5mg to 3.5mg per lation.[1, 107] day recommended for patients with severe liver insufficiency. Product information: De- creased clearance by 40% and prolonged t1/2 (>10h) in patients with liver disease. Rec- ommended dose reduction of 50%. Contra- indicated in patients with severe liver insufficiency. Personal recommendation: Accord- ing to pharmacokinetic data and data from clinical studies start with 50% of the recommended dose and adjust dosage according to dose-dependent adverse reactions. Antidepressants Amitriptyline Me Hydroxyla- 1 16 95 14 48 51 0.94 Rare: hepa- anticholinergic effects Studies: Altered kinetics (plasma levels and tion tocellular (dry mouth, sweating, AUC 2-3 times higher) and strong sedative (CYP2D6), and choles- confusion, constipa- response in a patient with porto-caval anas- N- tatic liver tion, blurred vision, tomosissonal recommendation: and cirrhosis.[109] Caution in patients demethyla- injury.[1, 4] urinary retention), with porto-caval shunts. Product information: tion sedation, tremor, Caution in patients with liver disease. Per- (CYP3A4 to headache, sexual According to phar- nortrip- dysfunction, weight macokinetic data, start with 50% of normal tyline), con- gain, orthostatic hy- dose and adjust maintenance dose accord- jugation.[2] potension, sinus ing to clinical effect and dose-dependent tachycardia, impaired adverse effects. AV-conduction, seizures[1, 2]

51 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Bupropion Hi Hydroxyla- >0.95 21 84 28 160 >0.9 Rare: ab- seizures, agitation, Studies: Only t1/2 of hydroxybupropion was tion to hy- normal liver insomnia, tremor, significantly prolonged (32 h vs 21 h; p<0.05) droxybu- tests, jaun- headache, anxiety, in patients with alcoholic liver disease com- propion dice, hepa- confusion, dizziness, pared with healthy volunteers.[112] AUC was [1, 110, formation: (active) by titis. nausea, vomiting, higher for bupropion and hydroxybupropion CYP 2B6, 111] constipation, weight but did not reach significance. Product in- reduction to loss, anorexia, dry No significant difference in the threohydro- mouth, tachycardia, pharmacokinetics between patients with mild bupropion hypertension[1-3] to moderate liver cirrhosis and healthy con- and trols. Cmax increased by 70%, t1/2 by 40% and erythrohy- AUC increased 3-fold in patients with severe drobu- liver cirrhosis compared with healthy con- propion trols. T1/2 of metabolites prolonged about 2- (both ac- to 4-fold. Contraindicated in patients with tive).[8] severe liver cirrhosis. Recommended daily dose for patients with mild to moderate liver disease 150mg. Personal recommendation: According to pharmacokinetic data and clinical studies, start with lowest available dose (150mg/d) and adjust maintenance dose or dosage interval according to dose- dependent adverse reactions. Because of expected increase in bioavailability, bupropion should be avoided in patients with severe liver cirrhosis (Child-Pugh class C).

52 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Citalopram Lo N- 0.85 33 80 14 80 18.1 0.28 Case re- headache, increased Studies: Oral clearance reduced by 36% in demethyla- port: hepa- sweating, dry mouth, cirrhotics and t1/2 about twice that of normal [115] tion, N- tocellular nausea, diarrhoea, subjects,information: accumulation possible. Lower oxidation injury.[114] constipation, vomiting, urinary excretion of desmethylcitalopram and and deami- dizziness, insomnia, didesmethylcitalopram observed. Product nation by somnolence, tachy- T1/2 prolonged about 2-fold and CYP 2C19, cardia, paraesthesia, steady state concentration increased twice in 3A4 and sexual dysfunction, patients with liver insufficiency. In patients 2D6[2, 113] to serotonin syndrome[1, withmendation: liver cirrhosis maintenance dose should active me- 2, 8] not exceed 10-30 mg/d. Personal recom- tabolites According to pharmacokinetic desmethyl- data and clinical studies, maintenance dose citalopram, should be reduced by 50% and adjusted dides- according to dose-dependent adverse reac- methylcita- tions. lopram, and citalopram- N-oxide.[3] Clomiprami Me Hydroxyla- 1 20 98 15 48 45 0.8 Occasion- anticholinergic effects Studies: No clinical studies available in pa- ne tion by CYP ally: hepa- (dry mouth, sweating, tients with liver disease. Product information: 2D6, de- tocellular confusion, constipa- Caution in patients with severe liver insuffi- methylation injury.[1] tion, blurred vision, ciency. Personal recommendation: Accord- to active Rare: liver urinary retention), ing to kinetic behaviour, initial doses should metabolite failure.[1] sexual dysfunction, be reduced by 50% and maintenance dose (N- weight gain, or- adjusted according to clinical effects and Desmethyl- thostatic hypotension, dose-dependent adverse reactions. clomipramin sinus tachycardia, e) by CYP impaired AV- 3A4, CYP conduction, seizures, 2C19 and increased prolactin CYP 1A2, release (gynaecomas- glucuronida- tia, galactorrhoea)[1, 2] tion.[1, 2]

53 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Dibenzepin Hi N- 1 5 85 4.2 25 ataxia, hypotension, Studies: No clinical studies available in pa- demethyla- tachycardia, impaired tients with liver disease. Product information: tion to ac- AV-conduction, anti- Caution in patients with liver insufficiency. tive metabo- cholinergic effects (dry Personal recommendation: According to lite.[1] mouth, blurred vision, pharmacokinetic data, initial doses should urinary retention, not exceed 25% of normal in patients with sweating, constipa- liver cirrhosis. Maintenance doses should be tion), hyperthermia, adjusted according to clinical effect and seizures, respiratory dose-dependent adverse reactions. depression[1, 6] Doxepin Hi Demethylati 1 17 95 20 27 65 >0.9 Rare: drowsiness, head- Studies: No clinical studies available in pa- on, N- hyper- ache, confusion, ex- tients with liver disease. Product information: oxidation, bilirubinae- trapyramidal symp- Cautionsonal recommendation: in patients with liver disease. Dose hydroxylatio mia,[1] cho- toms, ataxia, seizure, adjustment is recommended in patients with n, lestatic agitation, insomnia, severe liver disease (no specification). Per- glucuronidat and/or anticholinergic effects Based on the phar- ion;[1, 2] hepatocel- (dry mouth, sweating, macokinetic data, start with lowest possible active lular liver confusion, constipa- dose (10mg/d). Adjust maintenance dose metabolite: injury.[4] tion, blurred vision, according to clinical effect and dose- desmethyld urinary retention), dependent adverse reactions. oxepin.[1] hypotension, tachycardia, arrhythmia, gynaecomastia, galactorrhoea, hyperthermia[1, 2]

54 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Escitalo- Me N- 0.9 30 56 19 36 0.6 Frequency nausea, vomiting, Studies: AUC increased by 51% in patients pram demethyla- unknown: diarrhoea, dry mouth, with mild and 69% in patients with moderate tion by CYP abnormal insomnia, somno- hepaticuct information: impairment after a 20mg single oral 2C19, 2D6 liver func- lence, dizziness, fa- dose.[117] No serious adverse events re- and 3A4 to tion tests tigue, sexual dysfunc- ported. Recommended dose 10mg/d. Prod- des- tion, increased sweat- T1/2 increased by 100% and methylesci- ing, serotonin syn- AUC by 60% in patients with mild to moder- talopram drome[1, 3] ate liver insufficiency compared with healthy and dides- controls. Recommended initial dose 5mg methylesci- daily during the first 2 weeks. Increase dos- talopram age according to clinical effect to 10mg daily. (both Personal recommendation: According to weakly ac- pharmacokinetic data and clinical studies, tive), start with 50% of the recommended dosage deamina- and adjust maintenance dose according to tion, dehy- dose-dependent adverse reactions. drogenation, N-oxidation and glucuronida- tion.[1, 116] Fluoxetine Lo N- 0.97 48 94 30 >85 20 0.36 Rare: hepa- nausea, vomiting, Studies: Increased t1/2 of fluoxetine (from 2-3 demethyla- tocellular diarrhoea, headache, days to 7 days) and of norfluoxetine (from 6- tion to nor- injury, hy- insomnia, nervous- 9 days to 12 days) in patients with alcoholic [119, 120] fluoxetine per- ness, dizziness, liver cirrhosis. Vd of fluoxetine and (active me- bilirubinae- drowsiness, fatigue, norfluoxetine increased by 46% (p>0.05) and tabolite) mia.[1, 4] anxiety, tremor, sei- 50% (p=0.004), plasma clearance decreased (CYP2D6).[2] Case re- zure, asthenia, sweat- significantly by 56% and 30% in patients with ports: ele- ing, dry mouth, visual alcoholic liver cirrhosis compared with vations of disturbances, sexual healthy controls.[120] PB was similar in both bilirubin, dysfunction, tachycar- groups. Product information: T1/2 of fluoxet- transami- dia, serotonin syn- ine and norfluoxetine increased to 7.6 days nases, AP drome[1, 2, 6, 8] and 12 days, respectively. Use 20 mg every and other day. Personal recommendation: Ac- γGT.[118] cording to pharmacokinetic data, maintenance dose should be reduced by 50% or dosage interval increased from 1 to 2 days.

55 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Fluvoxam- Me Oxidation, 0.9 15 77 25 53 80 >0.9 Rare: ele- dry mouth, nausea, Studies: AUC increased by 50% due to [121] ine demethyla- vation of vomiting, diarrhoea, longer t1/2 (25h) in cirrhotic patients com- tion, and liver en- constipation, head- pared with data from healthy volunteers deamination zymes (no ache, dizziness, som- studied in a similar protocol.[123] Initiation of (CYP specifica- nolence, asthenia, treatmentinformation: at a lower daily dose was recom- 2D6).[1, 2] tion).[1] insomnia, anxiety, mended with careful monitoring of the patient Case re- tremor, sweating, during subsequent dose increases. Product port: eleva- tachycardia, palpita- recommendation: Clearance was decreased by tion of tion, hypotension, 30% in patients with hepatic insufficiency.[3] γGT.[122] sexual dysfunction, Start treatment with lower doses.[1] Personal serotonin syndrome[1, According to pharmacoki- 2, 8] netic data, start with 50% of normal dose and adjust dosage according to dose- dependent adverse reactions. Imipramine Me N- 1 16 85 15 44[125] 54.6 >0.9 Sporadic: anticholinergic effects Studies: No clinical studies available in pa- demethyla- cholestatic (dry mouth, sweating, tients with liver disease. Product information: tion to de- and hepa- confusion, constipa- Caution in patients with severe liver disease. sipramine tocellular tion, blurred vision, Personal recommendation: Considering the (active me- liver in- urinary retention), pharmacokinetic data, initial dose should not tabolite) and jury.[1, 4] fatigue, sexual dys- exceed 50% of normal. Adjust maintenance hydroxyla- function, weight gain, dose according to dose-dependent adverse tion to ac- orthostatic hypoten- reactions. tive metabo- sion, sinus tachycar- lites[2] by dia, impaired AV- CYP 2C19, conduction, seizures[1, 1A2, 2D6 2] and 3A4.[124]

56 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Maprotiline Me N- 1 45 90 25 68 32.4 0.6 Sporadic: drowsiness, dizziness, Studies: No clinical studies available in pa- demethyla- hepatocel- headache, tremor, tients with liver disease. Product information: tion to ac- lular injury, anticholinergic effects Contraindicated in patients with severe liver tive N- steatosis, (dry mouth, blurred disease. Personal recommendation: Accord- desmethyl- phosphol- vision, constipation, ing to pharmacokinetic data, reduce initial maprotiline ipidosis.[4] urinary retention, dose by 50% and adjust maintenance dose (CYP 2D6 sweating), changes in according to dose-dependent adverse reac- (major), weight, orthostatic tions. CYP 1A2 hypotension, sinus (minor)),[126] tachycardia, arrhyth- deamina- mia, palpitations, gy- tion, aro- naecomastia, galac- matic and torrhoea, seizures[1, 2] aliphatic hydroxylation and formation of aromatic methoxy derivatives.[2] Melitracen Nk Hydroxyla- 0.7 19 89 Sporadic: insomnia, dizziness, Studies: No clinical studies available in pation, N- cases of tremor, agitation, anti- tients with liver disease. Product information: demethyla- cholestatic cholinergic effects (dry Caution in patients with severe liver disease. tion to litra- liver in- mouth, sweating, con- Personal recommendation: Because of lack cen (active jury.[1] fusion, constipation, of pharmacokinetic data, no dose recom- metabo- blurred vision, urinary mendation can be made. Avoid in patients lite).[1] retention), orthostatic with liver cirrhosis. hypotension, tachycardia, AV block[1, 3]

57 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Mian- Hi CYP 0.95 33 95 15.7 25 19 i.v. 0.34 Cases: drowsiness, sedation, Studies: No clinical studies available in pa- serin[127] 2D6,[128] N- (oral mixed he- dizziness, weight gain, tients with liver disease. Product information: oxidation, Clsys patic injury, few anticholinergic Mianserintion: is contraindicated in patients with hydroxyla- higher) cholestatic effects (dry mouth, severe liver disease. Personal recommendation to ac- liver dis- visual disturbances, According to pharmacokinetic data, tive metabo- ease,[129] constipation, urinary start with lowest possible dose (15mg/d). lite (8- elevated retention, sweating), Adjust maintenance dose according to dose- hy- liver en- orthostatic hypoten- dependent adverse reactions. droxymian- zymes.[1] sion, sinus tachycar- serin), N- dia, arrhythmia, palpi- demethyla- tations, seizures[1, 2] tion des- methylmian- serin (active).[2] Mirtazapine Me Demethyla- 1 30 85 4.8 50 31 0.57 Sporadic: drowsiness, dizziness, Studies: After single dose (15 mg) of mirta- tion to ac- increase in sedation, weight gain, zapine in 2 age-matched parallel groups oral tive metabo- transami- few anticholinergic clearance was decreased by 33% and t1/2 lite (de- nases.[1] effects (dry mouth, increased by 39% in patients with hepatic methylmir- Case re- visual disturbances, impairment (not specified).[131] Dosage ad- tazapine) by port: mixed constipation), sinus justment may be necessary in patients with CYP 3A4, liver in- tachycardia, palpita- hepatic impairment. Product information: [130] hydroxyla- jury. tions, orthostatic hy- AUC and t1/2 increased by 50% in patients tion by potension[1] with mild and moderate liver insufficiency. CYP1A2 Caution in patients with liver insufficiency. and CYP Personal recommendation: According to 2D6, N- pharmacokinetic data, start with 50% of oxidation by normal dose (15mg/d). Adjust maintenance CYP3A4.[1] dose according to dose-dependent adverse reactions. Mo- Me Oxidation, 1 1.7 50 1.2 60 50 0.9 Case re- dizziness, headache, Studies: Decrease in systemic clearance by clobemide aromatic port: cho- anxiety, confusion, 61% (14.6 vs 37.7 l/h) after 90 mg i.v. and by hydroxyla- lestatic liver insomnia, sleep dis- 75% (20.2 vs 78.8 l/h) after 100 mg p.o. as [133] tion, deami- injury. turbances, nausea, well as prolongation in t1/2 by 129% (3.9 vs nation by few anticholinergic 1.7 h) and increase in bioavailability (84 vs CYP 2C19 effects (constipation, 56%) in patients with liver cirrhosis com- and CYP dry mouth, sweating, pared with healthy subjects.[134] A 2- to 3-fold 2D6.[132] visual disturbances), reduction in moclobemide dosage or alterna-

58 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects hypertension (exces- tively prolongation of dosage interval was sive amounts of recommended. Product information: Reduc- tyramine-rich food tion of daily dose to 33-50% of normal dos- should be avoided)[1, 2] age in patients with severe liver insufficiency. Personal recommendation: According to pharmacokinetic data and clinical studies, initial dose should be reduced by 50%. Ad- just maintenance dose according to dose- dependent adverse reactions. Alternatively double dosage interval. Nortriptyline Me Demethyla- 1 31 95 18 51 30 0.56 Occasion- anticholinergic effects Studies: No clinical studies available in pation, hy- ally: hepa- (dry mouth, sweating, tients with liver disease. Product information: droxylation tocellular confusion, constipa- Caution in patients with liver insufficiency. to 10- liver in- tion, blurred vision, Personal recommendation: According to the hydroxynor- jury.[4] urinary retention), pharmacokinetic data, start with 50% of triptyline drowsiness, sexual normal dose. Adjust maintenance dose ac- (active) by dysfunction, sinus cording to dose-dependent adverse reac- CYP 2D6,[2] tachycardia, impaired tions. partial bil- AV-conduction, sei- iary excre- zures, gynaecomastia, tion.[135] galactorrhoea, weight gain[1, 2] Opipramol Nk CYP 2D6,[1] 0.9 8 91 10 Sporadic: sedation, anticholiner- Studies: No clinical studies available in pa- metabolized jaundice,[1] gic effects (dry mouth, tients with liver disease. Product information: to deshy- hepatocel- blurred vision, consti- Caution in patients with severe liver insuffi- droxyethy- lular in- pation, urinary reten- ciency. Start with low initial doses and adjust lopipramol[1] jury.[136] tion, sweating), or- dosage according to dose-dependent ad- thostatic hypotension, versetion: reactions. Monitor liver function during sinus tachycardia, long-term treatment. Personal recommenda- impaired AV- Because of lack of pharmacokinetic conduction, seizures[1] data, no dose recommendation can be made. Oxitrip- Me Decarboxy- nk 4.4 60 0.9 49 11.9 nausea, vomiting, Studies: No clinical studies available in pa- tan[137] lation to diarrhoea, anorexia, tients with liver disease. Product information: [1, 3] serotonin by mental stimulation Cautionrecommendation: in patients with alcoholic liver cirrho- 5- sis and deficiency of vitamin B6 due to im- hydroxytryp- pairment of tryptophan metabolism. Personal tophande- Because of lack of data,

59 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects carboxy- no dose recommendations can be made. lase.[1] Note: Avoid in patients with liver cirrhosis. Pharma- cokinetic data of oxitriptan displayed after administration of a decarboxylase inhibitor. Paroxetine Me Oxidation by 0.96 17 95 13 50 36.1 0.64 Rare: hepa- nausea, diarrhoea, Studies: Doubled plasma levels and AUC in [2] [138] CYP 2D6. tocellular constipation, somno- patients with alcoholic liver cirrhosis. T1/2 and mixed lence, insomnia, dizzi- prolonged in patients with liver cirrhosis liver in- ness, asthenia, compared with healthy volunteers (83 vs jury.[1, 4] tremor, dry mouth, 36h), but difference was not statistically sig- sweating, tachycardia, nificant. Paroxetine dose should be at the hypotension, sexual lower end of normal for subjects with liver dysfunction, serotonin disease. Product information: Higher plasma syndrome[1, 2, 8] concentrations in patients with severe liver disease. Use doses at the lower range of normal. In patients with severe hepatic impairment initial doses of 10mg/d are recom- mendeddation: with increases in doses to maximal 40mg/d, if indicated.[8] Personal recommen- According to pharmacokinetic and clinical data, start with 50% of normal dose and adjust dosage according to dose- dependent adverse reactions.

60 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Reboxetine Lo Hydroxyla- 0.9 13 97 0.5 94 2 0.03 headache, insomnia, Studies: Compared with young healthy vol- tion, O- dizziness, tremor, unteers from a similar study AUC was up to dealkylation, hypertension, tachy- 92% higher and terminal t1/2 up to 150% oxidation of cardia, increased longer in patients with liver cirrhosis (Child- the mor- sweating, nausea, Pugh class B and C) after a single 4mg [140] pholine constipation, dry dose. Cmax was not significantly different ring.[1, 139] mouth, urinary reten- compared with healthy controls. A lower Metabolism tion, sexual dysfunc- starting dose of 4mg/day in divided doses is primarily via tion[1, 3] recommended. Product information: AUC CYP 3A4. increased by 92% in patients with liver insufficiency (Child-Pugh class B and C). No in- creaserecommendation: in Cmax. Recommended dosage 2mg twice daily. Increase dosage according to dose-dependent adverse reactions. Personal According to pharmacokinetic data and clinical studies, maintenance dose of 4mg daily in divided doses is recommended. Adjust maintenance dose according to dose-dependent adverse reactions.

61 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects

Sertraline Hi N- 1 23 98 25 96 >0.9 Rare: hepa- nausea, diarrhoea, Studies: AUC increased 4 times, t1/2 2.5 demethyla- tocellular weight loss, somno- times and Cmax 1.7 times in patients with liver tion by CYP injury.[4] lence, insomnia, nerv- cirrhosis after intake of 100mg sertraline as a [142] 2D6, 2C9, Case re- ousness, agitation, single oral dose. Cmax of desmethylser- 2B6, 2C19 ports: liver headache, dizziness, traline was 1.5-fold decreased (p<0.05) and [1] and 3A4 to failure. tremor, seizure, dry tmax significantly longer. Significant correla- active N- mouth, sweating, tion between sertraline plasma concentration desmethyl- tachycardia, sexual and serum albumin levels. It was recom- sertraline dysfunction, serotonin mended to start with 50mg sertraline per day (major syndrome[1, 2] and increase dosage only after 15 days, if pathway), necessary. Product information: Start treat- further ser- ment in patients with liver cirrhosis Child– traline un- Pughrecommendation: class A and B with 50% of normal ini- dergoes tial dose. Contraindicated in patients with hydroxyla- liver cirrhosis Child-Pugh class C. Personal tion, oxida- According to pharmacoki- tive deami- netic data and product information, it is rec- nation and ommended to start with 50% of normal dose N- (25mg/d). Adjust maintenance dose accord- carbamoyl ing to dose-dependent adverse reactions. Do glucuronida- not up-titrate the dose before 2 weeks after tion.[141] treatment beginning or dose adjustment. Trazodone Lo Hydroxyla- 1 6 95 0.8 75 8.8 0.16 Rare: cho- drowsiness, dizziness, Studies: No clinical studies available in pation, splitting lestatic headache, decreased tients with liver disease. Product information: of the pyri- and/or concentration, im- Caution in patients with liver disease. Titrate dine ring, hepatocel- paired memory, nau- dosage carefully. Personal recommendation: and epoxi- lular injury, sea, vomiting, diar- According to pharmacokinetic data, start with dation fol- chronic rhoea, constipation, an initial dose in the lower range of normal lowed by hepatitis.[4] tremor, blurred vision, and adjust maintenance dose according to hydrolysis. hypotension, arrhyth- clinical effect and dose-dependent adverse Metabolism mia, sexual dysfunc- reactions. via CYP tion, priapism[1, 2] 3A4 and 2D6. Active metabolite: 1-m- chloro- phenylpiper

62 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects azine.[1-3] Trimipramin Me Metabolized 0.9 23 90 31 41 67 >0.9 Rare: jaun- anticholinergic effects Studies: No clinical studies available in pa- e by CYP dice, eleva- (dry mouth, sweating, tients with liver disease. Product information: 2D6, 2C19 tions in liver confusion, constipa- Caution in patients with severe liver insuffi- and enzymes[1] tion, blurred vision, ciency. Personal recommendation: Accord- 3A4/5.[143] urinary retention), ing to pharmacokinetic data, initial dose Hydroxyla- sexual dysfunction, should not exceed 50% of normal dose. Ad- tion to 2- weight gain, or- just maintenance dose according to dose- hydroxy- thostatic hypotension, dependent adverse effects. trimipramine sinus tachycardia, , demethyla- impaired AV- tion to des- conduction, gynaeco- methyl- mastia, galactor- trimipramine rhoea[1, 2] (active) followed by glucuronida- tion.[1, 2] Venlafaxine Me Major path- 0.95 5 27 6 40[144] 91 >0.9 Rare: ab- nausea, vomiting, Studies: No clinical studies available in pa- way: O- normal liver asthenia, constipation, tients with liver disease. Product information: demethyla- function anorexia, weight loss, T1/2 of venlafaxine and O- tion (CYP tests, hepa- somnolence, dizzi- desmethylvenlafaxine prolonged by 30% and 2D6) to O- tocellular ness, anxiety, insom- 60%, respectively, in patients with liver cir- desmethyl- injury, cho- nia, dry mouth, sweat- rhosis compared with healthy persons. venlafaxine lestatic liver ing, tremor, nervous- Clearance was decreased by 50% and 30%, (active), injury, ness, blurred vision, respectively. Patients with severe liver cir- minor path- jaundice, hypertension, tachy- rhosis (Child-Pugh class C) had a more sub- way: N- hepatitis.[1, cardia, sexual dys- stantial decrease in clearance (about 90%). demethyla- 145, 146] function, seizures[1, 2] For patients with mild to moderate liver im- tion (CYP pairment dosage should be reduced by 50%. 3A3/4),[1, 2] In patients with liver cirrhosis dosage reduc- followed by tion of more than 50% may be necessary. glucuronida- Personal recommendation: According to tion-[2] pharmacokinetic data and indications in the product information, initial dose should be reduced by at least 50%. Adjust maintenance dose according to clinical effect and dose-dependent adverse reactions.

63 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Anti-Dementia drugs Donepezil Lo O- 0.95 70 96 12 100 9.1 0.16 nausea, diarrhoea, Studies: AUC doubled in female patients dealkylation, insomnia, vomiting, with cirrhosis Child-Pugh class A and B. hydroxyla- muscle cramps, syn- AUC increased 48%, Cmax 39%, and t1/2 tion, N- cope, dizziness, 54% in patients with cirrhosis Child-Pugh oxidation blurred vision, hy- class A or B following multiple doses of (CYP 2D6 potension, bradycar- donepezil 5mg compared with healthy volun- and CYP dia, diaphoresis, sali- teers.[148] Unbound fraction higher at day 27 3A4), hy- vation, nocturia[1, 8] (24.8% vs 21.4%; p=0.046). No serious ad- drolysis and verse events reported. Another study glucuronida- showed no significant differences in pharma- tion.[1, 147] cokinetics between patients with stable liver cirrhosis and normal subjects,[149] except for an increase in Cmax by 38%. Donepezil was well tolerated by all subjects. Both studies concluded that cirrhotics (Child–Pugh class A and B) may be safely treated with donepezil 5 mg daily. Product information: Clear- ance reduced by 20% in patients with alcoholic cirrhosis. Start with normal initial doses (5mg). However, donepezil is contraindicated in patients with liver cirrhosis Child– Pugh class C. Personal recommendation: According to the pharmacokinetic data and clinical studies, start with normal initial dose (5mg) and adjust maintenance dose according to clinical effects and dose-related adverse effects.

64 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects Galan- Lo N-oxidation, 0.8 7.5 18 2.5 88.5 18 0.27 nausea, vomiting, Studies: Pharmacokinetics of galantamine in tamine N- diarrhoea, abdominal subjects with mild hepatic impairment similar demethyla- pain, anorexia, weight to healthy subjects.[151] In patients with mod- tion, O- loss, drowsiness, diz- erate liver disease (Child-Pugh class B) in- demethyla- ziness, somnolence, crease in AUC by 33%, t1/2 by 30% and de- tion (CYP insomnia, headache, crease in total plasma clearance by 23%. No 2D6, 3A), syncope, bradycardia, dose adjustment necessary in subjects with glucuronida- hypotension[1, 8] liver cirrhosis Child-Pugh class A, cautious tion, epimer- dose titration in patients with Child-Pugh isation, ac- class B. Product information: Pharmacoki- tive metabo- netics not altered in patients with liver cirrho- lites,[1] 0.2% sis Child-Pugh class A compared with of galan- healthy volunteers. AUC and t1/2 increased tamine by 30% in patients with liver cirrhosis Child- eliminated Pugh class B. In patients with moderately by biliary impaired hepatic function (Child-Pugh class excre- B) treatment should be started with 8mg tion.[150] every 2 days during one week, continued by 8mg daily during 4 weeks. The maintenance doserecommendation: should not exceed 16mg daily. Galan- tamine is contraindicated in patients with liver cirrhosis Child-Pugh class C. Personal Adjust dosage according to product information. Memantine Lo Glucuroni- 0.5 80 45 10 100 10.2 0.09 dizziness, somno- Studies: No clinical studies available in pa- dation, hy- lence, headache, ab- tients with liver disease. Product information: droxylation, normal gait, restless- In patients with mild to moderate liver insuffi- N- ness, hallucinations, ciency no relevant changes in pharmacoki- oxida- vomiting, constipation, netics expected. Personal recommendation: tion.[152] hypertension[1, 3, 8, 152] According to pharmacokinetic data, start with Metabolism recommended initial dose of 5mg/d and ad- via CYP just maintenance dose according to dose- P450 mi- dependent adverse effects. nor.[1] Rivastig- Hi Metabolism 1 1 40 2 36 70 >0.9 Sporadic: nausea, vomiting, Studies: No clinical studies available in pa- mine by choli- abnormal diarrhoea, dyspepsia, tients with liver disease. Product information: nesterase- liver func- anorexia, weight loss, Reduction of clearance and increase in AUC mediated tion tests.[1] asthenia, fatigue, by factor 2 in patients with liver cirrhosis after

65 b Drug Drug Metabolism Q0 t1/2 [h] PB Vd F [%] Clsys E Hepatic Dose-dependent Studies performed and dosage recom- cat.a [%] [L/kg] [L/h] adverse adverse reactions mendations effects hydrolysis to sweating, dizziness, 3mg rivastigmine. However, dosage was well decarbamy- headache, tremor, tolerated and no dose adjustment was nec- lated me- depression, bradycar- essary. After administration of 6mg once or tabolite dia[1, 8] twice a day AUC increased by 100 to 210% (minimally and clearance decreased by 46% to 70% in active).[1] patients with liver insufficiency compared Non linear with healthy volunteers. No increase in inci- pharma- dence or severity of adverse effects was cokinetics, observed. No dose adjustment necessary in saturable patients with mild to moderate liver insuffi- metabolism. ciency. Adjust dosage according to individual tolerability. Contraindicated in patients with severe liver insufficiency, because of lack of data. Personal recommendation: According to pharmacokinetic data, initial dose should be reduced by 50%. Initial dose of 3mg was tolerated by patients with mild to moderate liver insufficiency, this dose can be chosen. Up-titrate slowly according to dose- dependent adverse reactions.

a Drug categories: Hi = high extraction drugs: hepatic extraction >60%, oral bioavailability <40% in case of complete intestinal absorp-

tion (or lower, if intestinal absorption is not complete). Me = intermediate extraction drugs: hepatic extraction 30-60%, oral bioavailability 40-

70%. Lo = low extraction drugs: hepatic extraction <30%, oral bioavailability >70%. In this category, protein binding may be relevant: for drugs

with high binding to albumin, hepatic clearance may increase. Nk = hepatic extraction not classifiable due to lack of pharmacokinetic data.

b E = Hepatic extraction was calculated as follows:

Cl Q × Cl E = hep = 0 sys Q Q

66 Clhep = hepatic clearance; Q0 = dose fraction metabolised or excreted extra-renally; Clsys = systemic plasma clearance; Q = plasma flow across the liver assumed to be 900 mL/min

ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; AUC = area under the concentration-time curve; Clsys = systemic clearance; Cmax = maximum concentration; CYP = cytochrome P450; DDCI = dopa decarboxylase inhibitor; E = hepatic extraction; F = bioavailability; γGT = gamma-glutamyl transpeptidase; i.v. = intravenous; nk = not known; PB = fraction bound to proteins; p.o. = peroral; Q0 = fraction metabolised or excreted by bile (1-Q0: fraction excreted unchanged by the kidney); SD = single dose; t1/2 = domi- nant half-life; tmax = time to reach maximal plasma concentration; var = variable; Vd = volume of distribution; for calculation of volume of distribution, bodyweight was assumed to be 70kg.

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