Prokinetic drugs

    Child-Pugh A Child-Pugh B Child-Pugh C
Metoclopramide Safety no additional risks known no additional risks known no additional risks known
Dose dose adjustment is not necessary use half of the normal dose use half of the normal dose
Domperidone Safety no additional risks known no additional risks known unsafe
Dose dose adjustment is not necessary use a third of the normal dose no dosing advice (unsafe)
Explanation

There were multiple studies retrieved where metoclopramide was used in patients with cirrhosis. Exposure to metoclopramide is approximately doubled in Child-Pugh B and C, so it is advised to use half of the normal dose. Domperidone is not well studied in patients with cirrhosis. Exposure is increased threefold in Child-Pugh B and it is recommended to use a third of the normal dose. There were no clinical studies in patients with Child-Pugh C cirrhosis and it is predicted that exposure increases. For these reasons it is classified as 'unsafe' in Child-Pugh C. 

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

Summary of literature

Considerations

The pharmacokinetics of metoclopramide were examined in four studies (level of evidence: 3, 4) with 37 cirrhotic subjects. Exposure to metoclopramide is in Child-Pugh (CTP) A cirrhosis comparable to healthy controls and there is no dose adjustment necessary. Exposure increases approximately twofold in CTP B and C cirrhosis. It is recommended to use half of the normal dose in these patients. Ten studies (level of evidence 2-4) looked at the safety of metoclopramide in 108 cirrhotic patients (CTP A/B/C 8/12/2; n=86 unknown). The occurring adverse events were similar to healthy controls. Metoclopramide is classified as ‘no additional risks known’. An increase in aldosterone could cause fluid accumulation in cirrhotic patients and metoclopramide should be stopped if this occurs. Metoclopramide is not recommended for patients suffering from gynaecomastia, because it can increase prolactin.

No pharmacokinetic studies were found where domperidone was used in cirrhotic patients. The product information does describe a study of the manufacturer, which found comparable pharmacokinetics in patients with CTP A cirrhosis and healthy controls. In CTP B patients, exposure increased by 190% and the free fraction by 25%. In a modelling study, an increase of 87% in exposure in CTP A was predicted, 206% in CTP B and almost 400% in CTP C. Two single-dose studies (level of evidence 2) were included that looked at the safety of domperidone in 22 patients with cirrhosis (CTP A/B/C 5/6/1, 10 unknown). Domperidone was tolerated well after a single-dose. Domperidone is classified as ‘no additional risks known’ in CTP A cirrhosis and no dose adjustment is recommended. In CTP B it is also classified as ‘no additional risks known’ if the dose is reduced to a third of the normal dose. Based on the (predicted) highly altered exposure in CTP C patients and the limited clinical data, it is classified as ‘unsafe’.

Pharmacokinetic data

  • Absorption: Metoclopramide has a variable bioavailability of 60-100%. One pharmacokinetic study found 60% higher maximum plasma concentrations (Cmax) in patients with CTP C cirrhosis. The bioavailability of domperidone is low (approx. 15%), caused by a high first-pass effect. There were no studies found with domperidone in cirrhotic patients. The product information describes a study were Cmax was 50% higher in patients with CTP B compared to healthy controls. There were no differences found for CTP A patients.
  • Distribution: 13-22% of metoclopramide is bound to plasma proteins. The volume of distribution was no different in patients with cirrhosis in two studies. Domperidone is highly protein bound (91-93%). The free fraction increased by 25% in patients with CTP B cirrhosis (product information).
  • Metabolism: Metoclopramide is metabolized to a sulphur conjugate. None of the pharmacokinetic studies also measured this metabolite. Domperidone is subject to extensive metabolism in the liver by hydroxylation and N-dealkylation (CYP3A4, CYP1A2 and CYP2E1).  No data are available on this metabolism in cirrhosis.
  • Elimination: Metoclopramide is mainly renally excreted with an elimination half-life of 5-6 hours. In two studies, clearance of metoclopramide was significantly reduced in patients with cirrhosis. The elimination half-life was prolonged to 15.4 hours in patients with CTP C cirrhosis. Domperidone is excreted in bile for 66% with an elimination half-life of 7-9 hours. According to the product information, elimination half-life was prolonged to 23 hours in patients with CTP B. 
  • Exposure: Exposure to metoclopramide was comparable to healthy controls in one pharmacokinetic study, while it was increased in three other studies. In a study with CTP C patients, AUC was found to be 126% higher in the cirrhotic patients. A pharmacokinetic modelling study predicted an increase in AUC of 22% in CTP A, 88% in CTP B and 158% in CTP C. Exposure to unbound metoclopramide was even more increased (+38% CTP A, 119% CTP B and 211% CTP C). The last study observed an increase of 54% in exposure in patients without ascites and 70% in patients with ascites. Exposure to domperidone was slightly decreased in CTP A patients compared to healthy controls and increased by 190% in patients with CTP B. The modelling study predicted a 87% enlargement in exposure to unbound domperidone in CTP A, a tripled exposure in CTP C and a five-fold increased exposure in CTP C.

 

Safety data

Multiple studies assess the safety of metoclopramide in patients with cirrhosis. Metoclopramide is tolerated well in most and only mild adverse events occurred. It was also noted that metoclopramide can increase aldosterone and prolactin concentrations, which can have more severe consequences in cirrhotic patients (i.e. fluid accumulation, worsening of gynaecomastia). In a case-report a cirrhotic patient suffered from extrapyramidal side effects after using 20 mg metoclopramide for four days.

Domperidone was used by cirrhotic patients in two studies and was well tolerated in a single dose of 10 mg.