Other calcium channel blockers

    Child-Pugh A+B Child-Pugh C
Diltiazem Safety no additional risks known no additional risks known
Dose start with half of the normal dose and increase slowly start with half of the normal dose and increase slowly
Verapamil Safety no additional risks known unsafe
Dose (PO) start with an initial dose of 40 mg twice daily and increase slowly with a dosing interval of 12 hours.  no dosing advice (unsafe)
Dose (IV)

use a third of the normal maintenance dose

no dosing advice (unsafe)
Explanation

Diltiazem and verapamil are extensively cleared by the liver. For both drugs case-reports are available in which a cardiogenic shock occurred in patients with cirrhosis. In some this happened after insertion of a transjugular intrahepatic shunt (TIPS). Diltiazem and verapamil need to be carefully used in patients with cirrhosis. There is not much data about the pharmacokinetics of diltiazem in cirrhosis and it is recommended to start carefully with half of the normal dose. More research has been done with verapamil in patients with cirrhosis. The elimination half-life and exposure to verapamil both largely increased compared to healthy controls. For these reasons, it is advised to start very low when using verapamil in patients with Child-Pugh A and B cirrhosis. Verapamil is not recommended in patients with Child-Pugh C. Retard formulations of verapamil are not suited for use in patients with cirrhosis.

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

Summary of literature

Considerations

Diltiazem is extensively hepatically cleared, but only one pharmacokinetic study (evidence level 3) has been performed with diltiazem in patients with cirrhosis (n=7). Diltiazem has a large first-pass effect and insertion of a transjugular intrahepatic shunt (TIPS) could cause a large increase in exposure. In one case-report a cardiogenic shock occurred after TIPS insertion. The product information describes that the exposure in cirrhotics is increased by 70%. An expert opinion in a review advises to use half of the normal starting dose and we adopt this advice. In adjusted dose, it is classified as ‘no additional risks known’.

Five studies (evidence level 3-4) have assessed pharmacokinetics of verapamil in 41 patients with cirrhosis. After an oral dose, the bioavailability was increased probably caused by a diminished first-pass effect. The elimination half-life was fourfold prolonged after oral and intravenous administration. Exposure was threefold increased after intravenous administration, compared to healthy controls. None of the studies classified patients according to their Child-Pugh score. However, in one study patients with severe varices bleeding were included which probably are patients with severe cirrhosis. Peak plasma levels were sevenfold higher in these patients than in healthy controls. In four case-reports (level 4) a cardiogenic shock occurred after verapamil administration in cirrhotics. It is advised to start very low with oral dosing in patients with CTP A and B (⅓ to ¼ of the normal dose, i.e. 40 mg twice daily). Increase the dose using a dosing interval of 12 hours. Long-acting verapamil is not appropriate for this. For intravenous use, it is advised to use a maintenance dose of one-third of the normal dose. When the dose is adjusted, it is classified as ‘no additional risks known’ in CTP A and B cirrhosis. In patients with CTP C, an even higher increase in exposure is expected and the use comprises high safety risks, therefore it is classified as unsafe. 

Pharmacokinetic data

  • Absorption: Diltiazem and verapamil both have a large first first-pass effect (F= 40% and 33% respectively). The FDA label of diltiazem describes a 70% increase in bioavailability in patients with cirrhosis compared to healthy controls. The bioavailability of verapamil was in a study 52% in patients with cirrhosis versus 22% in healthy controls. The peak plasma levels were seven times higher in patients undergoing TIPS insertion compared to healthy controls.
  • Distribution: Diltiazem is 80-85% bound to plasma proteins and verapamil 90%. Both are bound to both albumin and α1-glycoprotein. The volume of distribution of verapamil was increased in two studies among patients with cirrhosis.
  • Metabolism: Diltiazem and verapamil are both extensively metabolized in the liver. Diltiazem is converted to multiple metabolites and the two main metabolites possess 50% and 20% of the activity of diltiazem. The exposure to the most active metabolite (N-demethyldiltiazem), formed by CYP3A4 enzymes, was slightly decreased. Exposure to the other main metabolite (deacetyldiltiazem), formed by esterases, was more than doubled compared to healthy controls. Verapamil has 12 known metabolites, with as main active metabolite norverapamil (20% activity of verapamil).
  • Elimination: Diltiazem is mostly excreted in faeces (about 65%). In a study the elimination half-life of diltiazem was 7 hours in patients with cirrhosis and 5 hours in healthy controls. Verapamil is for 50-70% excreted in urine. Elimination half-life was 13-14 hours in patients with cirrhosis compared to 3-4 hours in healthy controls. Clearance was also reduced, in one study it was halved in cirrhotics, in another it was one-third and in the last it was one-fifth of the clearance of healthy controls.
  • Exposure: Exposure to diltiazem was examined in one study in which the AUC until 7 hours after administration was determined. The AUC was slightly increased (+15%), but because it was only determined for 7 hours and the elimination half-life was prolonged, the AUC until infinity could have been more increased. Exposure to verapamil was only measured in one study where an increase of 226% was found in patients with cirrhosis. 

Safety

Diltiazem was well tolerated in a pharmacokinetic study among seven patients with cirrhosis. In two case-reports diltiazem was also used in patients with cirrhosis. In one of these, intravenous diltiazem (0.25 mg/kg bolus and 10 mg/h infusion) caused hypotension in a patient with mild cirrhosis. The hypotension developed into a hypoxic hepatitis. In the other case-report a patient with CTP B underwent a TIPS placement and developed a cardiogenic shock 3 days after. This was probably caused by long-acting diltiazem 300 mg in combination with propranolol 30 mg per day.

Verapamil caused a cardiogenic shock in 4 cirrhotic patients in case-reports. In one of these, the shock occurred after TIPS insertion and the administration of 120 mg verapamil retard in patient with CTP A. In another of these case-reports verapamil 160 mg was used in combination with atenolol. In the remaining two, verapamil alone in a dose of 240 mg was used. A possibly lethal verapamil level (1.9 mg/L) was measured in one of these patients. In three other clinical studies, verapamil decreased blood pressure and heartrate after a single-dose.