OCALIVA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for OCALIVA (OCALIVA).
Ocaliva (obeticholic acid) is a farnesoid X receptor (FXR) agonist. FXR is a nuclear receptor that regulates bile acid synthesis, transport, and homeostasis. Activation of FXR reduces the production of bile acids by suppressing cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis, and increases the expression of FXR target genes involved in bile acid transport and detoxification.
| Metabolism | Obeticholic acid is metabolized in the liver and intestine via conjugation with glycine or taurine, and subsequently undergoes extensive enterohepatic recirculation. It is not significantly metabolized by CYP450 enzymes. The conjugated metabolites are eliminated in feces. |
| Excretion | Following oral administration, approximately 87% of the dose is excreted in feces (primarily as unchanged drug and metabolites) and less than 3% is excreted renally. Biliary excretion is the major route for the parent drug and its conjugates. |
| Half-life | The terminal elimination half-life of obeticholic acid is approximately 24 hours for the parent drug and 3.5 to 5.8 days for its active conjugates (glyco- and tauro-obeticholic acid). This long half-life supports once-daily dosing but indicates that steady-state is reached after about 2 weeks. |
| Protein binding | Obeticholic acid is approximately 99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | The volume of distribution is approximately 6.5 L/kg, indicating extensive extravascular distribution, consistent with its lipophilic nature and high tissue binding, particularly to liver and intestinal tissues. |
| Bioavailability | Absolute bioavailability of oral obeticholic acid is approximately 50%, with a range of 30-70% due to first-pass hepatic metabolism and conjugation. |
| Onset of Action | Clinical improvement in pruritus and reduction in alkaline phosphatase (ALP) levels are observed within 1 to 2 weeks of initiating therapy, with maximal effect on ALP typically seen after 3 to 6 months of treatment. |
| Duration of Action | The duration of action, based on pharmacodynamic effects (FXR activation), lasts throughout the dosing interval of 24 hours. Sustained suppression of bile acid synthesis persists for the duration of therapy; effects wane over several days after discontinuation due to the long half-life of active conjugates. |
5 mg orally once daily, increase to 10 mg once daily if adequate response after 3 months.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended in severe renal impairment (eGFR <30 mL/min/1.73 m2). |
| Liver impairment | Child-Pugh class A: No adjustment. Child-Pugh class B: Initial dose 5 mg once daily, increase to 10 mg if tolerated. Child-Pugh class C: Contraindicated. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment; use caution due to potential for increased exposure and hepatic impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for OCALIVA (OCALIVA).
| Breastfeeding | It is not known whether obeticholic acid is excreted in human milk. In animal studies, obeticholic acid and/or its metabolites were detected in milk of lactating rats. The M/P ratio is not available. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ocaliva, women should not breastfeed during treatment and for 3 weeks after the last dose. |
| Teratogenic Risk | There are no adequate and well-controlled studies of Ocaliva in pregnant women. In animal reproduction studies, oral administration of obeticholic acid to pregnant rats and rabbits during organogenesis at doses less than the maximum recommended human dose (MRHD) resulted in embryofetal mortality and malformations. Based on animal data, Ocaliva may cause fetal harm when administered to a pregnant woman. Avoid use during pregnancy, especially in the first trimester, unless the potential benefit to the mother outweighs the potential risk to the fetus. |
■ FDA Black Box Warning
WARNING: HEPATIC DECOMPENSATION AND LIVER FAILURE IN INCORRECTLY DOSED PBC PATIENTS WITH CHILD-PUGH CLASS B OR DECOMPENSATED CIRRHOSIS. Patients with Child-Pugh class B or decompensated cirrhosis (Child-Pugh class C) are at increased risk of hepatic decompensation and liver failure when incorrectly dosed. Ocaliva is contraindicated in patients with decompensated cirrhosis (Child-Pugh class C). In patients with Child-Pugh class B, the starting dose is 5 mg once weekly, with dose adjustment based on response and tolerability.
| Serious Effects |
["Complete biliary obstruction","Decompensated cirrhosis (Child-Pugh class C)","Known hypersensitivity to obeticholic acid or any component of the formulation"]
| Precautions | ["Hepatic decompensation and liver failure in patients with Child-Pugh class B or decompensated cirrhosis","Risk of hepatic decompensation in patients with moderate to severe hepatic impairment","Severe pruritus: dose reduction, antihistamines, or bile acid resins may be considered","Reduction in HDL-C levels; monitor lipid levels periodically","Monitor liver function tests (e.g., bilirubin, INR) and signs of hepatic decompensation"] |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST, alkaline phosphatase, bilirubin) and bile acids monthly during pregnancy. In patients with pre-existing hepatic impairment, more frequent monitoring may be necessary. Fetal ultrasound monitoring for growth and anatomy should be considered. Monitor for signs of worsening hepatic function or pruritus. |
| Fertility Effects | No human data are available regarding the effect of Ocaliva on fertility. In animal studies, obeticholic acid had no effect on fertility in male and female rats at doses up to 50 mg/kg/day (approximately 5 times the MRHD based on AUC). |