Ocaliva

Name: Ocaliva

Pharmacology

Mechanism of Action

Farnesoid X receptor (FXR) agonist

FXR is a nuclear receptor expressed in the liver, intestine, kidney, and adipose tissue that regulates a wide variety of target genes critically involved in the control of bile acid synthesis and transport, lipid metabolism, and glucose homeostasis

FXR activation suppresses de novo synthesis of bile acids in hepatocytes as well as increasing transport of bile acids out of hepatocytes, thereby reducing exposure of the hepatocytes to bile acid

Absorption

Peak plasma concentration

  • Obeticholic acid: 1.5 hr
  • Active metabolites: 10 hr

Distribution

Protein bound: >99%

Vd: 618 L

Metabolism

Obeticholic acid is conjugated with glycine or taurine in the liver then secreted into bile

The conjugates are converted back to obeticholic acid and either reabsorbed in the small intestine for enterohepatic recirculation or excreted in feces

Elimination

Excretion: ~87% feces; <3% urine

Why is this medication prescribed?

Obeticholic acid is used alone or in combination with ursodiol (Actigall, Urso) to treat primary biliary cholangitis (PBC; a type of liver disease that destroys bile ducts, which allows bile to stay in the liver and cause damage) in patients who cannot take ursodiol or in patients who were not treated successfully with ursodiol alone. Obeticholic acid is in a class of medications called farnesoid X receptor agonists. It works by decreasing the production of bile in the liver and increasing the removal of bile from the liver.

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to obeticholic acid.

Before having any laboratory test, tell your doctor and the laboratory personnel that you are taking obeticholic acid.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Ocaliva Drug Class

Ocaliva is part of the drug class:

  • Bile acid preparations

Ocaliva Interactions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

  • bile acid binding resins such as cholestyramine, colestipol, or colesevelam. 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.
  • warfarin
  • CYP1A2 substrates with a narrow therapeutic index such as theophylline and tizanidine (Zanaflex)

This is not a complete list of Ocaliva drug interactions. Ask your doctor or pharmacist for more information.

 

Ocaliva Food Interactions

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Ocaliva, there are no specific foods that you must exclude from your diet when receiving this medication.

Ocaliva Overdose

If you take too much Ocaliva, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

What other drugs will affect obeticholic acid?

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • theophylline;

  • tizanidine; or

  • warfarin (Coumadin, Jantoven).

This list is not complete. Other drugs may interact with obeticholic acid, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Cautions for Ocaliva

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Complete biliary obstruction.1

Warnings/Precautions

Hepatic Effects

Dose-related adverse hepatic effects (e.g., jaundice, worsening ascites, primary biliary cholangitis flare) reported.1

Monitor patients for elevations in liver function tests and development of adverse hepatic effects.1 In patients experiencing clinically important hepatic effects (e.g., ascites, hepatic encephalopathy), weigh potential benefits of drug against possible risks.1

Do not exceed maximum recommended dosage of 10 mg daily.1 Adjust dosage in patients with moderate or severe hepatic impairment.1 (See Special Populations under Dosage and Administration.) Discontinue drug in patients who develop complete biliary obstruction.1 (See Contraindications under Cautions.)

Severe Pruritus

Severe pruritus reported.1 Dose-related increases in incidence and severity of pruritus observed, particularly at dosages >10 mg daily.3

For patients experiencing severe pruritus, consider addition of antihistamine or bile acid sequestrant.1 (See Specific Drugs under Interactions.)

Dosage reduction of obeticholic acid with or without temporary interruption of therapy also may be considered.1 (See Dosage Modification for Severe Pruritus under Dosage and Administration.)

Lipid Effects

Reductions in HDL-cholesterol concentration observed.1 3

Monitor patients for changes in serum lipid concentrations.1 For patients experiencing reductions in HDL-cholesterol concentrations without an adequate response to obeticholic acid at the highest recommended, maximally tolerated dosage after 1 year of therapy, weigh potential benefits of drug against possible risks of continuing treatment.1

Specific Populations

Pregnancy

Limited data on obeticholic acid use during pregnancy inadequate to inform of drug-associated risk.1

No evidence of developmental abnormalities or fetal harm in animal studies.1

Lactation

Not known whether obeticholic acid distributes into human milk; effects of drug on breast-fed infants or milk production also not known.1

Consider benefits of breast-feeding and the woman's clinical need for the drug; also consider potential adverse effects on breast-fed infant from drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1

Geriatric Use

No overall differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Increased exposure in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Absorption: Special Populations, under Pharmacokinetics.)

Use contraindicated in patients with complete biliary obstruction.1

Renal Impairment

Population analysis indicates that pharmacokinetics not altered by estimated GFR >50 mL/minute per 1.73 m2.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Not studied in patients with moderate or severe renal impairment (estimated GFR <60 mL/minute per 1.73 m2).1

Common Adverse Effects

Pruritus,1 3 fatigue,1 3 nasopharyngitis,3 abdominal pain/discomfort,1 rash,1 arthralgia,1 3 oropharyngeal pain,1 dizziness,1 constipation,1 peripheral edema,1 palpitations,1 pyrexia,1 thyroid function abnormality,1 eczema.1

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of advising patients to report immediately to their clinician any symptoms of worsening liver disease or symptoms of complete biliary obstruction.1 Periodic laboratory testing may be warranted to assess liver function and/or monitor for changes in serum lipid concentrations.1

  • Importance of advising patients to contact their clinician if they experience pruritus or an increase in severity of pruritus.1

  • Importance of informing patients that obeticholic acid may be taken without regard to meals.1

  • Importance of taking obeticholic acid at least 4 hours (or as long an interval as possible) before or after taking a bile acid sequestrant.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., bile acid sequestrants, warfarin) and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).1

  • Importance of advising women to inform clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Proper Use of Ocaliva

Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Take this medicine with or without food.

If you are taking cholestyramine, colestipol, or colesevelam, take Ocaliva™ at least 4 hours before or 4 hours after these medicines.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For treatment of primary biliary cholangitis:
      • Adults—At first, 5 milligrams (mg) once a day. Your doctor may adjust your dose as needed and tolerated. However, the dose is not more than 10 mg once a day.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Ocaliva Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common
  • Fever
  • severe itching skin
Incidence not known
  • Abdominal or stomach pain
  • chills
  • clay-colored stools
  • dark urine
  • dizziness
  • headache
  • loss of appetite
  • nausea
  • rash
  • stomach pain and bloating
  • unpleasant breath odor
  • unusual tiredness or weakness
  • vomiting of blood
  • yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Abdominal or stomach discomfort
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • difficulty having a bowel movement (stool)
  • difficulty with moving
  • fast, irregular, pounding, or racing heartbeat or pulse
  • muscle pain or stiffness
  • pain in the joints
  • rapid weight gain
  • sore throat
  • tingling of the hands or feet
  • unusual weight gain or loss
Less common
  • Skin rash, encrusted, scaly and oozing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Uses of Ocaliva

  • It is used to treat a certain bile duct problem (cholangitis).

Drug Interactions

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 (2.4)].

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.

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.

Ocaliva - Clinical Pharmacology

Mechanism of Action

Obeticholic acid is an agonist for FXR, a nuclear receptor expressed in the liver and intestine. FXR is a key regulator of bile acid, inflammatory, fibrotic, and metabolic pathways. FXR activation decreases the intracellular hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol as well as by increased transport of bile acids out of the hepatocytes. These mechanisms limit the overall size of the circulating bile acid pool while promoting choleresis, thus reducing hepatic exposure to bile acids.

Pharmacodynamics

Dose Titration

In Trial 1, ALP reduction was observed to plateau at approximately 3 months in most patients treated with Ocaliva 5 mg once daily. Increasing the dosage of Ocaliva to 10 mg once daily based on tolerability and response provided additional reduction in ALP in the majority of patients [see Dosage and Administration (2.1), Clinical Studies (14)].

Pharmacodynamic Markers

In Trial 1, administration of Ocaliva 10 mg once daily was associated with a 173% increase in concentrations of FGF-19, an FXR-inducible enterokine involved in bile acid homeostasis, from baseline to Month 12. Concentrations of cholic acid and chenodeoxycholic acid were reduced 2.7 micromolar and 1.4 micromolar, respectively, from baseline to Month 12. The clinical relevance of these findings is unknown.

Cardiac Electrophysiology

At a dose of 10-times the maximum recommended dose, Ocaliva does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption

Following multiple oral doses of Ocaliva 10 mg once daily, peak plasma concentrations (Cmax) of obeticholic acid occurred at a median time (Tmax) of approximately 1.5 hours. The median Tmax for both the glyco- and tauro-conjugates of obeticholic acid was 10 hours. Coadministration with food did not alter the extent of absorption of obeticholic acid [see Dosage and Administration (2.4)].

Following multiple-dose administration of Ocaliva 5, 10, and 25 mg once daily (2.5 times the highest recommend dosage) for 14 days, systemic exposures of obeticholic acid increased dose proportionally. Exposures to glyco-obeticholic acid and tauro-obeticholic acid, and total obeticholic acid (the sum of obeticholic acid and its two active conjugates) increased more than proportionally with dose.

Distribution

Human plasma protein binding of obeticholic acid and its conjugates is greater than 99%. The volume of distribution of obeticholic acid is 618 L. The volumes of distribution of glyco- and tauro-obeticholic acid have not been determined.

Elimination

Metabolism

Obeticholic acid is conjugated with glycine or taurine in the liver and secreted into bile. These glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine leading to enterohepatic recirculation. The conjugates can be deconjugated in the ileum and colon by intestinal microbiota, leading to the conversion to obeticholic acid that can be reabsorbed or excreted in feces, the principal route of elimination.

After daily administration of obeticholic acid, there was accumulation of the glycine and taurine conjugates of obeticholic acid, which have in vitro pharmacological activities similar to the parent drug, obeticholic acid. The metabolite-to-parent ratios of the glycine and taurine conjugates of obeticholic acid were 13.8 and 12.3 respectively, after daily administration. An additional third obeticholic acid metabolite, 3-glucuronide, was formed but was considered to have minimal pharmacologic activity.

Excretion

After administration of radiolabeled obeticholic acid, about 87% of the dose was excreted in feces through biliary secretion. Less than 3% of the dose was excreted in the urine with no detection of obeticholic acid.

Specific Populations

Age, Sex Race/Ethnicity: Based on population pharmacokinetic analysis, the pharmacokinetics of obeticholic acid would not be expected to be altered based on age, sex, or race/ethnicity.

Renal Impairment: Obeticholic acid has not been studied in patients with moderate and severe renal impairment (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m2). In the population pharmacokinetic analysis, an eGFR greater than 50 mL/min/1.73 m2 did not have a meaningful effect on the pharmacokinetics of obeticholic acid and its conjugated metabolites.

Hepatic Impairment: Obeticholic acid is metabolized in the liver. In subjects with mild, moderate and severe hepatic impairment (Child-Pugh Class A, B, and C, respectively), the mean AUC of total obeticholic acid increased by 1.1-, 4- and 17-fold, respectively, compared to subjects with normal hepatic function following single-dose administration of 10 mg Ocaliva [see Dosage and Administration (2.3), Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Obeticholic Acid on Other Drugs

Based on in vitro studies, obeticholic acid can inhibit CYP3A4. However, an in vivo study indicated no inhibition of CYP3A4 by obeticholic acid at the recommended dose of Ocaliva. Obeticholic acid is not expected to inhibit CYPs 2B6, 2C8, 2C9, 2C19, and 2D6, or induce CYPs 1A2, 2B6, 2C8, 2C9, 2C19, and 3A4 at the recommended dose of Ocaliva. Down-regulation of mRNA was observed in a concentration-dependent fashion for CYP1A2 and CYP3A4 by obeticholic acid and its glycine and taurine conjugates.

In vitro studies suggest that there is potential for obeticholic acid and its glycine and taurine conjugates to inhibit OATP1B1 and OATP1B3 (the clinical significance of which is unknown), but not P-gp, BCRP, OAT1, OAT3, OCT2, and MATE transporters, at the recommended dose of Ocaliva.

Warfarin: Concomitant administration of 25 mg warfarin as a single dose with Ocaliva 10 mg once daily resulted in 13% increase in systemic exposure to S-warfarin and 11% decrease in maximum INR [see Drug Interactions (7.2)].

Caffeine (CYP1A2 substrate): Concomitant administration of 200 mg caffeine as a single dose with Ocaliva 10 mg once daily resulted in a 42% increase in plasma AUC and 6% increase in Cmax of caffeine [see Drug Interactions (7.3)].

Omeprazole (CYP2C19 substrate): Concomitant administration of 20 mg omeprazole as a single dose with Ocaliva 10 mg once daily resulted in a 32% increase in AUC and a 33% increase in Cmax of omeprazole. The clinical significance is unknown.

No clinically relevant interactions were seen when the following drugs were administered as single doses concomitantly with Ocaliva 10 mg once daily:

Midazolam 2 mg (CYP3A4 substrate): 2% increase in AUC and Cmax of midazolam.

Dextromethorphan 30 mg (CYP2D6 substrate): 11% decrease in AUC and 12% decrease in Cmax of dextromethorphan.

Digoxin 0.25 mg (P-gp substrate): 1% increase in AUC and 3% decrease in Cmax of digoxin.

Rosuvastatin 20 mg (BCRP, OATP1B1, OATP1B3 substrate): 22% increase in AUC and a 27% increase in Cmax of rosuvastatin.

Effect of Other Drugs on Obeticholic Acid

In vitro data suggest that obeticholic acid is not metabolized to any significant extent by CYP450 enzymes.

Proton Pump Inhibitors (omeprazole): Concomitant administration of 20 mg omeprazole once daily with Ocaliva 10 mg once daily resulted in a less than 1.2-fold increase in obeticholic acid exposure. This increase is not expected to be clinically relevant. Concomitant administration of 40 mg omeprazole once daily with Ocaliva 10 mg once daily was not studied.

Clinical Studies

The recommended starting dosage of Ocaliva is 5 mg orally once daily for 3 months with titration to 10 mg once daily based upon tolerability and response [see Dosage and Administration (2.1)]. Initiation of therapy with a starting dosage Ocaliva 10 mg once daily is not recommended due to an increased risk of pruritus [see Adverse Reactions (6.1)].

Trial 1 was a randomized, double-blind, placebo-controlled, 12-month trial which evaluated the safety and efficacy of Ocaliva in 216 patients with PBC who were taking UDCA for at least 12 months (on a stable dosage for at least 3 months), or who were unable to tolerate UDCA and did not receive UDCA for at least 3 months. Patients were included in the trial if the ALP was 1.67-times upper limit of normal (ULN) or greater and/or if total bilirubin was greater than 1-times ULN but less than 2-times ULN. Patients were excluded from the trial if they had other liver disease, presence of clinically significant hepatic decompensation events (i.e., portal hypertension and its complications, cirrhosis with complications, or hepato-renal syndrome), severe pruritus, or Model for End Stage Liver Disease (MELD) score of 15 or greater.

Patients were randomized (1:1:1) to receive either Ocaliva 10 mg once daily for the entire 12 months of the trial, (n=73); Ocaliva titration (5 mg once daily for the initial 6 months, with the option to increase to 10 mg once daily for the last 6 months if the patient was tolerating Ocaliva but had ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction) (n=70); or placebo (n=73). Ocaliva or placebo was administered in combination with UDCA in 93% of patients during the trial and as monotherapy in 7% of patients who were unable to tolerate UDCA.

The primary endpoint was a responder analysis at Month 12, where response was defined as a composite of three criteria: ALP less than 1.67-times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%. The ULN for ALP was defined as 118 U/L for females and 124 U/L for males. The ULN for total bilirubin was defined as 1.1 mg/dL for females and 1.5 mg/dL for males.

The study population was 91% female and 94% white. The mean age was 56 years (range 29 to 86 years). The mean baseline ALP concentration was 323.2 U/L, corresponding to 2.74-times ULN. Approximately 29% of the patients had ALP concentration levels greater than 3-times the ULN. The mean baseline total bilirubin concentration was 0.65 mg/dL, and was less than or equal to the ULN in 92% of the enrolled patients. Distribution of patients by Rotterdam disease stage criteria at baseline is shown in Table 2. Cirrhosis was present at baseline in 4 patients (5%) in the Ocaliva 10 mg arm, 7 patients (10%) in the Ocaliva titration arm, and 9 patients (12%) in the placebo arm.

Table 2: Rotterdam Disease Stage Criteria at Baseline in Trial 1 by Treatment Arm with or without UDCA *
Disease Stage† Ocaliva 10 mg
(N=73)
Ocaliva Titration
(N=70)
Placebo
(N=73)
Percentages are based on non-missing values for each time point.
* In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%) in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm. † Early: normal total bilirubin and normal albumin (values less than or equal to ULN and greater than or equal to the lower limit of normal (LLN), respectively), Moderately advanced: abnormal total bilirubin or abnormal albumin, Advanced: abnormal total bilirubin and abnormal albumin. Total bilirubin ULN: 1.1 mg/dL (females) and 1.5 mg/dL (males). Albumin LLN: 35 g/L (females and males).
Early, n (%) 66 (90) 64 (91) 65 (89)
Moderately Advanced, n (%) 7 (10) 6 (9) 8 (11)
Advanced, n (%) 0 (0) 0 (0) 0 (0)

Table 3 shows the percentage of patients by treatment arm in Trial 1 who achieved a response to the primary composite endpoint at Month 12, and to the individual components of the primary endpoint (i.e., ALP less than 1.67-times the ULN, total bilirubin less than or equal to ULN, and an ALP decrease of at least 15%). A total of 33 patients in the Ocaliva titration arm, who did not achieve a response at 6 months and tolerated Ocaliva, had their dosage increased from 5 mg once daily to 10 mg once daily. Of these 33 patients, 13 (39%) achieved the primary composite endpoint at 12 months.

Table 3: Percentage of Adult Patients with PBC Achieving the Primary Composite Endpoint at Month 12 in Trial 1 by Treatment Arm with or without UDCA*
Ocaliva
10 mg
(N = 73)
Ocaliva
Titration†
(N = 70)
Placebo
(N = 73)
* In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%) in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm. † Patients randomized to Ocaliva titration received Ocaliva 5 mg for the initial 6 month period. At Month 6, patients who were tolerating Ocaliva, but had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction were eligible for titration from 5 mg once daily to 10 mg once daily for the final 6 months of the trial. ‡ Percentage of patients achieving a response, defined as an ALP less than 1.67-times the ULN, total bilirubin less than or equal to the ULN, and an ALP decrease of at least 15%. Missing values were considered a non-response. The exact test was used to calculate the 95% CIs. § p<0.0001 for Ocaliva titration and Ocaliva 10 mg arms versus placebo. P-values are obtained using the Cochran–Mantel–Haenszel General Association test stratified by intolerance to UDCA and pretreatment ALP greater than 3-times ULN and/or AST greater than 2-times ULN and/or total bilirubin greater than ULN. ¶ Response rates were calculated based on the observed case analysis (i.e., [n=observed responder]/[N=ITT population]); percentage of patients with Month 12 values are 86%, 91% and 96% for the Ocaliva 10 mg, Ocaliva titration and placebo arms, respectively. # The mean baseline total bilirubin value was 0.65 mg/dL, and was less than or equal to the ULN in 92% of the enrolled patients.
Primary Composite Endpoint‡
  Responder rate, (%)§
  [95% CI]
48
[36, 60]
46
[34, 58]
10
[4, 19]
Components of Primary Endpoint¶
  ALP less than 1.67-times ULN, n (%) 40 (55) 33 (47) 12 (16)
  Decrease in ALP of at least 15%, n (%) 57 (78) 54 (77) 21 (29)
  Total bilirubin less than or equal to ULN#, n (%) 60 (82) 62 (89) 57 (78)

Mean Reduction in ALP

Figure 1 shows the mean reductions in ALP in Ocaliva-treated patients compared to placebo. Reductions were observed as early as Week 2, plateaued by Month 3 and were maintained through Month 12 for patients who were maintained on the same dosage throughout 12 months. Although Trial 1 studied titration at 6 months, these data are supportive of titration of Ocaliva after 3 months [see Dosage and Administration (2.1)]. For patients in the Ocaliva titration arm whose Ocaliva dosage was increased from 5 mg once daily to 10 mg once daily, additional reductions in ALP were observed at Month 12 in the majority of patients [see Clinical Pharmacology (12.2)].

Figure 1: Mean ALP over 12 Months in Trial 1 by Treatment Arm with or without UDCAa
a In the trial there were 16 patients (7%) who were intolerant and did not receive concomitant UDCA: 6 patients (8%) in the Ocaliva 10 mg arm, 5 patients (7%) in the Ocaliva titration arm, and 5 patients (7%) in the placebo arm. b Patients randomized to Ocaliva titration received Ocaliva 5 mg once daily for the initial 6 month period. At Month 6, patients who were tolerating Ocaliva, but had an ALP 1.67-times ULN or greater, and/or total bilirubin greater than ULN, or less than 15% ALP reduction were eligible for titration from 5 mg once daily to 10 mg once daily for the final 6 months of the trial.

Mean Reduction in GGT

The mean (95% CI) reduction in gamma-glutamyl transferase (GGT) was 178 (137, 219) U/L in the Ocaliva 10 mg arm, 138 (102, 174) U/L in the Ocaliva titration arm, and 8 (-32, 48) U/L in the placebo arm.

Ocaliva Monotherapy

Fifty-one PBC patients with baseline ALP 1.67-times ULN or greater and/or total bilirubin greater than ULN were evaluated for a biochemical response to Ocaliva as monotherapy (24 patients received Ocaliva 10 mg once daily and 27 patients received placebo) in a pooled analysis of data from Trial 1 and from a randomized, double-blind, placebo-controlled, 3-month trial. At Month 3, 9 (38%) Ocaliva-treated patients achieved a response to the composite endpoint, compared to 1 (4%) placebo-treated patient. The mean (95% CI) reduction in ALP in Ocaliva-treated patients was 246 (165, 327) U/L compared to an increase of 17 (-7, 42) U/L in the placebo-treated patients.

PRINCIPAL DISPLAY PANEL - 5 mg Tablet Bottle Label

NDC 69516-005-30
Rx only

Ocaliva®
(obeticholic acid) tablets

5 mg

30 tablets
Intercept

Ocaliva side effects

Get emergency medical help if you have signs of an allergic reaction to Ocaliva: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • severe itching;

  • rapid weight gain, especially in your face and midsection;

  • swelling in your ankles;

  • dark urine, clay-colored stools;

  • nausea, vomiting;

  • jaundice (yellowing of the skin or eyes);

  • tiredness, joint pain;

  • dry eyes or mouth;

  • darkening of your skin; or

  • puffiness around your eyes.

Common Ocaliva side effects may include:

  • itching, rash;

  • feeling tired;

  • sore throat;

  • stomach pain, constipation;

  • dizziness; or

  • joint pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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