Typical antipsychotics

      Child-Pugh A + B Child-Pugh C
Haloperidol Safety no additional risks known no additional risks known
Dose start with 50% of the normal dose start with 25% of the normal dose
Sulpiride Safety no additional risks known
Dose start at the lower end of the normal dosing range
Amisulpride Safety unknown 
Dose no dosing advice possible
Bromperidol Safety unknown 
Dose no dosing advice possible
Chlorprothixene Safety unknown 
Dose no dosing advice possible
Fluphenazine Safety unknown 
Dose no dosing advice possible
Flupenthixol Safety unknown 
Dose no dosing advice possible
Fluspirilene Safety unknown 
Dose no dosing advice possible
Penfluridol Safety unknown
Dose  no dosing advice possible 
Perphenazine Safety unknown 
Dose  no dosing advice possible 
Periciazine Safety  unknown 
Dose  no dosing advice possible 
Pimozide Safety  unknown 
Dose  no dosing advice possible 
Pipamperone Safety  unknown
Dose  no dosing advice possible 
Tiapride Safety  unknown 
Dose   no dosing advice possible
Zuclopentixol Safety  unknown 
Dose   no dosing advice possible 
Explanation

There is a lack of pharmacokinetic studies with typical antipsychotics in patients with cirrhosis. Most are cleared by the liver to a large extent, with amisulpride, sulpiride and tiapride as exceptions. Patients with cirrhosis can be more susceptible for the adverse drug reactions of antipsychotics (e.g., extrapyramidal symptoms and sedation). Furthermore, sedation and confusion can possibly increase the risk of hepatic encephalopathy or worsen it. Due to the lack of data no dose adjustment can be suggested for most of the antipsychotics. It is advised to start with the lowest possible dose and monitor efficacy and side effects, and if possible, also plasma levels. As amisulpride and tiapride are largely renally cleared, dose adjustments may not be needed for these medicines.

Information about the safety classification and the recommended actions can be found here.

 

Summary of literature

Considerations

Studies with haloperidol were most often found in literature, probably because this antipsychotic is most frequently prescribed. We found two pharmacokinetic studies (level 4) in 7 patients (severity unknown). The first was a PK modellings study predicting that exposure to haloperidol more than doubled in CTP B and was 3.5-fold increased in CTP C cirrhosis compared to healthy controls. The other study found a doubled unbound fraction of haloperidol in the blood of cirrhotics. An expert review suggested to reduce the initial dose of haloperidol with 50% and adjust maintenance dose according to adverse drug reactions. The product information also advises to use half of the normal dosage. In five case-reports (level 4) extrapyramidal symptoms and drowsiness occurred in cirrhotic patients on haloperidol (1 early cirrhosis, 1 advanced, rest unknown severity). We advise that haloperidol can be used (“no additional risks known”) if the starting dose is adjusted to 50% in CTP A and B and 25% in CTP C based on the predicted increases in exposure.

Sulpiride: in one study (level 3), prolactin release after sulpiride use was assessed in 20 patients with cirrhosis (n=5 with ascites) and compared to healthy controls. The peak prolactin levels were comparable. Sulpiride is only to a small extent metabolized by the liver and mainly renally excreted. An expert review advised that a dose adjustment may not be needed, while the SmPC recommends to dose sulpiride with caution. We evaluate sulpiride as ‘no additional risks known’, do not advise a dose adjustment but do advise to start with a dose at the lower end of the normal range.

Amisulpride: One case-report (level 4) was found in which a cirrhotic patient suffered from Pisa syndrome after three days amisulpride 200 mg per day. As a review also describes, amisulpride undergoes only modest hepatic metabolism. These experts advise to start with a dosage in the lower range of normal and adjust according to adverse drug reactions. We classify it as unknown because of too little data and therefore cannot give a dose recommendation.

Perphenazine: a pharmacokinetic modelling study predicted large AUC increases (+26% CTP A, +159% CTP B, +384% CTP C), corresponding to the large hepatic clearance of perphenazine. The expert review advised to start with the lowest possible dose (2 mg), while the SmPC and FDA label do not recommend to use perphenazine in these patients. We classify it as ‘unknown’ based on the lack of clinical data and therefore cannot give a dose recommendation.

Zuclopenthixol: a pharmacokinetic modelling study predicts moderate AUC increases (+11% CTP A, +51% CTP B, +77% CTP C) in cirrhosis, although zuclopenthixol is mainly metabolized in the liver and eliminated in the bile. The SmPC advises to dose cautiously and determine plasma levels if possible. The expert review suggests to start with 50% of the normal dose. We classify it as ‘unknown’ based on the lack of clinical data therefore cannot give a dose recommendation.

The antipsychotics chlorprothixene, flupenthixol, fluphenazine, penfluridol, pipamperone and tiapride all have no data, only an expert opinion in a review. All are classified as ‘unknown’. All except tiapride are largely hepatically cleared. Dose adjustments are probably needed, but due to a lack of data cannot be specified.

For the antipsychotics bromperidol, fluphenazine, fluspirilene, periciazine and pimozide no data or expert opinions are available. All are largely cleared by the liver and pharmacokinetic changes are expected in patients with cirrhosis. All SmPCs advise to dose cautiously. We classify them as ‘unknown’ and cannot give a specific dose advice.

Pharmacokinetic data

  • Absorption: Most of the typical antipsychotics do not have a high bioavailability when administered orally (F<30%: bromperidol, chlorprothixene, sulpiride, F=30-70%: amisulpride, flupenthixol, haloperidol, perphenazine, tiapride and zuclopenthixol, rest unknown). Some are subjected to a large first-pass effect as described in the product information (i.e. bromperidol, chlorprothixene, perphenazine). The following antipsychotics also have a high hepatic extraction ratio: bromperidol, chlorprothixene, fluphenazine and perphenazine. An intermediatie hepatic extraction ratio: amisulpride, flupenthixol, haloperidol, zuclopenthixol and a low hepatic extraction ratio: sulpiride, tiapride, penfluridol. The hepatic extraction ratio is unknown for: fluspirilene, periciazine, pimozide and pipamperone
  • Distribution: Amisulpride, pipamperone, sulpiride and tiapride all have low protein binding (<90%). The protein binding of periciazine and pimozide is unknown. The other antipsychotics are highly bound to plasma proteins (>90%). In a study, plasma protein binding of haloperidol was assessed in cirrhotics and compared to healthy controls. The unbound fraction haloperidol was 19% in the cirrhotic patients compared to 12% in young adults and 9% in elderly.  
  • Metabolism: Amisulpride, sulpiride and tiapride are all metabolised to a small extent. The other antipsychotics are all largely metabolised. None has a known active metabolite.
  • Elimination: Antipsychotics mostly renally eliminated are amisulpride, pimozide, pipamperone, sulpride and tiapride. Those with the largest part hepatically eliminated are: flupenthixol and zuclopenthixol. The antipsychotics with renal excretion as well as biliairy excretion are: bromperidol, chlorprothixene, haloperidol, penfluridol and periciazine. Excretion of the other antipsychotics is unknown.
  • Exposure: In a PK modelling study, exposure to haloperidol, perphenazine and zuclopenthixol was predicted as AUC ratio compared to healthy controls. The predicted AUC ratio of total haloperidol was: CTP A: 1.35, CTP B: 2.34 and CTP C: 3.56. For perphenazine this was CTP A: 1.26, CTP B: 2.59, CTP C: 4.84 and the AUC ratios for zuclopenthixol were: CTP A: 1.11, CTP B: 1.51 and CTP C: 1.77.

Safety data

A book and a review describe that patients with cirrhosis can be more susceptible for certain adverse drug reactions of antipsychotics (e.g. extrapyramidal symptoms), partly caused by altered pharmacokinetics. Furthermore, sedation and confusion can possibly increase the risk of hepatic encephalopathy or worsen it.

Haloperidol: five case-reports were retrieved in which adverse drug reactions occurred in patients while treated with haloperidol. In three movement disorders (e.g. extrapyramidal symptoms, parkinsonism) occurred in 3 patients (severity unknown) during treatment with haloperidol (1.5 mg-10 mg/d). In one, a patient with early cirrhosis suffered from neuromalignant syndrome and died, she used haloperidol (9 mg/d) in combination with an interacting medicine (phenelzine). In the last case report, a patient with cirrhosis and a TIPS developed excessive drowsiness after haloperidol 2 mg thrice daily. The dose was adjusted to 1 mg thrice daily and only mild drowsiness occurred. Haloperidol was later restarted in a dose of 1 mg four times daily, again excessive drowsiness occurred and the dose was adjusted to 1 mg twice daily.

Sulpiride: a study in 20 patients with cirrhosis (n=5 with ascites) assessed prolactin release after sulpiride and did not find differences in prolactin peak between patients with and without cirrhosis. Also, no difference were found between liver function parameters and the prolactin peak (albumin, gammaglobulin). In the patients with ascites, lower prolactin serum peaks were found, probably due to the distribution in the ascitic fluid.   

Amisulpride: one case report on a patient with CTP B cirrhosis describes occurrence of the pisa syndrome (dystonic spasms) after amisulpride use (200 mg/d).