Systemic antihistamines

      Child-Pugh A Child-Pugh B+C
Cetirizine Safety no additional risks known no additional risks known
Dose use half of the normal dose use half of the normal dose
Levocetirizine Safety no additional risks known no additional risks known
Dose use half of the normal dose use half of the normal dose
Desloratadine Safety no additional risks known no additional risks known
Dose use half of the normal dose use half of the normal dose
Loratadine Safety no additional risks known no additional risks known
Dose use half of the normal dose use half of the normal dose
Ebastine Safety no additional risks known no additional risks known
Dose no dose adjustment needed no dose adjustment needed
Fexofenadine Safety no additional risks known no additional risks known
Dose no dose adjustment needed no dose adjustment needed
Hydroxyzine Safety no additional risks known unknown
Dose no dose adjustment needed no dosing advice possible
Mizolastine  Safety no additional risks known unknown
Dose no dose adjustment needed no dosing advice possible
Acrivastine Safety unknown  unknown 
Dose  no dosing advice possible no dosing advice possible   
Alimemazine Safety unknown  unknown 
Dose   no dosing advice possible no dosing advice possible   
Chlorcyclizine Safety  unknown  unknown 
Dose  no dosing advice possible  no dosing advice possible   
Cinnarzine Safety   unknown unknown 
Dose   no dosing advice possible no dosing advice possible   
Clemastine Safety  unknown  unknown 
Dose   no dosing advice possible no dosing advice possible   
Cyclizine Safety   unknown unknown 
Dose   no dosing advice possible no dosing advice possible   
Dimetindene Safety  unknown  unknown 
Dose   no dosing advice possible no dosing advice possible   
Ketotifen Safety unknown  unknown 
Dose  no dosing advice possible no dosing advice possible   
Meclozine Safety unknown  unknown 
Dose  no dosing advice possible no dosing advice possible   
Oxomemazine Safety  unknown  unknown 
Dose  no dosing advice possible no dosing advice possible   
Promethazine Safety unknown  unknown 
Dose  no dosing advice possible no dosing advice possible   
Rupatadine Safety  unknown unknown 
Dose no dosing advice possible  no dosing advice possible 
Explanation
There is not much literature available about the pharmacokinetics of antihistamines in patients with cirrhosis. Studies have only been performed with cetirizine, desloratadine, ebastine, fexofenadine, hydroxyzine and mizolastine. Antihistamines are predominantly cleared by the liver and in most of the studies, pharmacokinetics are altered in patients with cirrhosis resulting in increased exposure. One study reported hepatic encephalopathy as a result of hydroxyzine treatment in one patient with severe cirrhosis, health care professionals need to be aware of this.

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

 

Summary of literature

Considerations

Pharmacokinetics of cetirizine were studied in two single-dose studies (evidence level 3-4) among five patients with cirrhosis (Child-Pugh A/B/C 1/3/1) and 11 patients with primary biliary cirrhosis. Although cetirizine is mainly renally cleared, exposure was approximately doubled in the two studies, while peak plasma levels were similar to controls. No adverse events occurred in one study, while all patients reported sedation in the other. Because of the doubled exposure in two studies it is recommended to use half of the normal dose to prevent excessive sedation. Cetirizine is classified as ‘no additional risks known’ if dose adjustments are adopted.

Levocetirizine has not been studied in patients with cirrhosis, although cetirizine (the racemic variant) has been studied. Therefore, dose recommendations from cetirizine are adopted and it also classified as ‘no additional risks known’.                                                                                                                       

Desloratadine pharmacokinetics were examined in one multiple-dose study (level 3) among 12 patients with CTP B cirrhosis. Exposure and peak plasma levels were doubled compared to controls. In a single-dose study described in the product information, exposure and peak plasma levels were also doubled in 12 patients with cirrhosis (4 patients per CTP-class). The EPAR does not advise dose recommendations, while the FDA label does. In the multiple-dose study both healthy controls and cirrhotic patients experienced adverse events, but drowsiness was most commonly reported in cirrhotics. We classify desloratadine as ‘no additional risks known’ and advise to use half of the normal dose for all CTP-classes.

Loratadine is the racemic mixture of desloratadine. It has not been studied in literature in patients with cirrhosis, although the product information describes a study performed in cirrhotic patients (n=7). Exposure and peak plasma levels of loratadine were doubled compared to healthy controls, while pharmacokinetics of desloratadine were not significantly altered. Elimination half-life of loratadine increased from 8 h to 24 h and that of desloratadine from 28 h to 37 h. The product information advises to use 10 mg every other day in patients with severe hepatic impairment. We classify it the same as desloratadine: ‘no additional risks known’ and advise to use half of the normal dose. 

In a multiple dose study (level 3, n=24; 8 per CTP class) and a single dose study (level 3, n=10) ebastine was studied in patients with cirrhosis. Peak plasma levels and exposure to ebastine were slightly increased compared to healthy controls, while exposure to the active metabolite carebastine was similar to healthy controls. There were mostly mild adverse events noted in these studies. The product information advises to use no more than 10 mg per day in patients with severe hepatic impairment. This dose adjustment is only based on the study where patients with CTP C used no more than 10 mg, so no experience with higher dosages. Exposure was however not different compared to healthy controls in this studie, so we do not recommend a dose adjustment. Ebastine is classified as ‘no additional risks known’

Fexofenadine pharmacokinetics were studied after a single 80 mg oral dose (level 4) in 17 patients with cirrhosis (n=10 CTP A, n=7 CTP B/C). Peak plasma levels and exposure were similar to healthy controls. Fexofenadine was also well tolerated. It is classified as ‘no additional risks known’ and no dose adjustments are recommended.

Hydroxyzine was studied in one pharmacokinetic article (level 4) among 8 patients with primary biliary cirrhosis (unknown if they suffered from cirrhosis; they had no hepatic encephalopathy or varices) and one randomized trial (level 2) in 17 patients with CTP B and C cirrhosis. Exposure was comparable to elderly controls, but larger when compared to younger controls. Elimination half-life was prolonged to 37 hours (14 h in adults). Anticholinergic adverse events occurred in six of the patients and all became sleepy (dose: 0.7 mg/kg IV). In the randomized trial 25 mg hydroxyzine was mostly well tolerated, except for one patient with severe cirrhosis and a TIPS who developed hepatic encephalopathy. There is no data about pharmacokinetics in patients with CTP B and C and therefore it is classified as ‘unknown’ for these patients. In CTP A it is classified as ‘no additional risks known’ and no dose adjustment is recommended.

Mizolastine is studied in 12 patients with cirrhosis (severity unknown) in a single-dose study (level 4). Exposure was increased by 50%, while elimination half-life was similar to healthy controls. The product information states that a significant impaired hepatic function is a contra-indication. It is classified as ‘no additional risks known’ in CTP A cirrhosis without a need for dose adjustment, and as ‘unknown’ in CTP B and C cirrhosis.

With acrivastine, alimemazine, chlorcyclizine, cinnarazine, clemastine, cyclizine, dimetindene, ketotifen, meclozine, oxomemazine, promethazine and rupatadine no studies in patients with cirrhosis have been performed, nor does the product information supplies information about use in cirrhotic patients. Therefore, all are classified as ‘unknown’ and it is advised to use a safer alternative. No dosage suggestion could be given.

Pharmacokinetic data

  • Absorption: There is not much known about the systemic availability of some antihistamines, because they are never intravenously administered. Most antihistamines are subject to first-pass metabolism, resulting in an incomplete systemic availability. Ketotifen and mizolastine have an intermediate bioavailability (F=50% and 65%) and promethazine a low (F=25%). In studies the peak plasma levels of cetirizine, ebastine, fexofenadine, and mizolastine were similar to healthy controls, while Cmax was doubled in CTP B patients using desloratadine and increased with 50% in patients using hydroxyzine.
  • Distribution: A few antihistamines are highly protein bound (fb ≥90% i.e. cetirizine, clemastine, ebastine, levocetirizine, loratadine, mizolastine and rupatadine), while acrivastine, cyclizine, desloratadine, fexofenadine, ketotifen and promethazine have a lower protein binding. For the remaining antihistamines it is unknown.
  • Metabolism: Most antihistamines are extensively metabolized in the liver, with as exceptions cetirizine, fexofenadine, levocetirizine and meclozine. Ebastine and loratadine both have a major metabolite responsible for most of the pharmacological effect.
  • Elimination: Cinnarazine, dimetindene, fexofenadine, meclozine and rupatadine are mainly excreted in faeces. Desloratadine, loratadine and promethazine are in similar parts excreted both in faeces and in urine. For mizolastine and chlorcyclizine the elimination pathways are unknown and for the remaining antihistamines renal excretion is the major elimination pathway. Elimination half-life of desloratadine and of cetirizine was prolonged in cirrhotics versus healthy controls (resp. 50 h vs. 34 h and 14 h vs. 9 h).
  • Exposure:       
  • Cetirizine: in two single-dose studies exposure was approximately doubled in patients with cirrhosis compared to healthy controls.           
  • Desloratadine: in one multiple-dosing study for 10 days in 12 patients with CTP B cirrhosis, exposure was doubled compared to healthy controls. Same results are described in the product information in a single-dose study.
  • Ebastine: in one single-dose and one multiple-dose study exposure was similar in patients with cirrhosis (even CTP C) and healthy controls.
  • Fexofenadine: in a single-dose study AUC in patients with cirrhosis (CTP A+B+C) was comparable to healthy controls.
  • Hydroxyzine: in one single-dose study patient with primary biliary cirrhosis (unknown if cirrhosis) had a similar exposure to hydroxyzine with healthy controls. The antihistaminergic effect was also similar.
  • Mizolastine: in a single dose study Cmax in patients with cirrhosis was comparable with healthy controls and exposure 50% increased.

Safety data

There was one randomized clinical trial with an antihistamine; hydroxyzine. One of the 17 patients developed an acute episode of hepatic encephalopathy after 8 days of 25 mg per day, with resolution of symptoms after cessation. He did have a previous episode of hepatic encephalopathy and had a TIPS.

In most pharmacokinetic studies adverse events were noted. In the study with hydroxyzine (0.7 mg/k IV), anticholinergic adverse events occurred in 6 of 8 patients (i.e. blurred vision, dry mouth and dizziness). Also, all patients became sleepy and 6 actually fell asleep. In one of the pharmacokinetic studies with cetirizine, no sedative effects were observed while in the other (with half of the dose), all patient (n=6) reported sedation and four fell asleep. In the pharmacokinetic study with desloratadine half of the subjects reported at least one treatment-emergent adverse event; headache and drowsiness were most commonly reported. Fexofenadine was well tolerated in the single-dose study. In the two studies with ebastine, only mild adverse events occurred (i.e. headache, somnolence, xerostomia and dyspepsia). Both studies described no cardiac adverse events (ECGs were similar, even as Qt-interval measured). One study also described that mild changes in liver functions test occurred, not further specified.