Ocaliva (Page 3 of 7)

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of OCALIVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure, particularly in PBC patients who have progressive liver disease.

Hepatobiliary Disorders: liver failure, new onset cirrhosis, increased direct and total bilirubin, new or worsening of jaundice [see Warnings and Precautions (5.1)].

7 DRUG INTERACTIONS

7.1 Bile Acid Binding Resins

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible [see Dosage and Administration (2.5)].

7.2 Warfarin

The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA [see Clinical Pharmacology (12.3)]. Monitor INR and adjust the dosage of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.

7.3 CYP1A2 Substrates with Narrow Therapeutic Index

Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates [see Clinical Pharmacology (12.3)]. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA.

7.4 Inhibitors of Bile Salt Efflux Pump

Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine [see Clinical Pharmacology (12.3)]. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The limited available human data on the use of obeticholic acid during pregnancy are not sufficient to inform a drug-associated risk. In animal reproduction studies, no developmental abnormalities or fetal harm was observed when pregnant rats or rabbits were administered obeticholic acid during the period of organogenesis at exposures approximately 13-times and 6-times human exposures, respectively, at the maximum recommended human dose (MRHD) of 10 mg [see Data below].

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryo-fetal development study in rats, obeticholic acid was administered orally during the period of organogenesis at doses of 5, 25, and 75 mg/kg/day. At 25 mg/kg/day (a dose that produced systemic exposures approximately 13-times those in humans at the MRHD of 10 mg), there was no maternal or developmental toxicity. At 75 mg/kg/day (approximately 40-times the human exposure at the MRHD), decreased fetal body weights and increased numbers of early or late resorptions and nonviable fetuses were observed. In maternal animals, mortality, fetal loss, decreased body weight and food consumption as well as decreased body weight gain were observed at 75 mg/kg/day. Thus, the developmental toxicity observed at this dose may be secondary to maternal toxicity. In rabbits, obeticholic acid was administered orally during the period of organogenesis at doses of 3, 9, and 20 mg/kg/day. Obeticholic acid administered at doses up to 20 mg/kg/day (approximately 6-times the human exposure at the MRHD) was not teratogenic and did not produce any evidence of fetal harm.

In a pre- and post-natal development study, administration of obeticholic acid in rats during organogenesis through lactation at doses of 5, 25, and 40 mg/kg/day did not produce effects on pregnancy, parturition, or postnatal development at any dose (the 40 mg/kg/day dose is approximately 21-times the human exposure at the MRHD).

Obeticholic acid exposure margins were calculated using systemic exposure (AUC) values of obeticholic acid plus obeticholic acid’s active metabolite conjugates (tauro-obeticholic acid and glyco-obeticholic acid) in animals (at the indicated doses) and in humans at the MRHD of 10 mg.

8.2 Lactation

Risk Summary

There is no information on the presence of obeticholic acid in human milk, the effects on the breast-fed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OCALIVA and any potential adverse effects on the breastfed infant from OCALIVA or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of OCALIVA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 201 patients in clinical trials of OCALIVA who received the recommended dosage (5 mg or 10 mg once daily), 41 (20%) were 65 years of age and older, while 9 (4%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and patients less than 65 years of age, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated [see Warnings and Precautions (5.1)]. OCALIVA is contraindicated in patients with decompensated cirrhosis (e.g., Child-Pugh Class B or C), in those with a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) [see Contraindications (4)].

In PBC clinical trials, a dose-response relationship was observed for the occurrence of hepatic adverse reactions with OCALIVA [see Warnings and Precautions (5.1)].

Plasma exposure to obeticholic acid and its active conjugates, increases significantly in patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].

Routinely monitor patients for progression of PBC with laboratory and clinical assessments. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease, and/or severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment. Interrupt treatment during severe intercurrent illness [see Dosage and Administration (2.3), Warnings and Precautions (5.1)].

10 OVERDOSAGE

In the clinical trials, PBC patients who received OCALIVA 25 mg once daily (2.5-times the highest recommended dosage) or 50 mg once daily (5-times the highest recommended dosage) experienced a dose-dependent increase in the incidence of hepatic adverse reactions, including elevations in liver biochemical tests, ascites, jaundice, portal hypertension, and primary biliary cholangitis flares.

Serious hepatic adverse reactions have been reported postmarketing in PBC patients with decompensated cirrhosis when OCALIVA was dosed more frequently than the recommended dosage; these adverse reactions were also reported in some patients who received the recommended dosage [see Contraindications (4), Warnings and Precautions (5.1)].

In the case of overdosage, patients should be carefully observed, and supportive care administered, as appropriate.

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