Obeticholic acid (Tablets) Instructions for Use

Marketing Authorization Holder

Salyutfarma, LLC (Russia)

Manufactured By

OHFK, JSC (Russia)

ATC Code

A05AA04 (Obeticholic acid)

Active Substance

Obeticholic acid (Rec.INN registered by WHO)

Dosage Forms

	Obeticholic acid	Film-coated tablets 5 mg
		Film-coated tablets 10 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

100 pcs. – jars – cardboard packs (100 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription

Film-coated tablets

100 pcs. – jars – cardboard packs (100 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription

Pharmacotherapeutic Group

Means for the treatment of diseases of the liver and biliary tract; agents for the treatment of diseases of the biliary tract; bile acids and their derivatives

Pharmacological Action

Obeticholic acid is a selective agonist of the farnesoid X receptor (FXR) – nuclear receptors located in the liver and intestine.

FXR is a key regulator of bile acid metabolism, as well as inflammatory, fibrotic, and metabolic responses.

Activation of FXR reduces the intracellular concentration of bile acids by suppressing de novo synthesis from cholesterol, and by increasing the transport of bile acids from hepatocytes.

These mechanisms limit the overall size of the circulating bile acid pool, promoting choleresis, thereby reducing the exposure of the liver to bile acids.

Pharmacokinetics

After oral administration, Obeticholic acid is well absorbed from the gastrointestinal tract, with C_max in plasma reached in approximately 2 hours.

Concomitant administration of obeticholic acid with food does not affect the extent of absorption.

After multiple administration of 5, 10, and 25 mg of obeticholic acid once daily for 14 days, C_ss increases proportionally to the dose.

The binding to human plasma proteins of obeticholic acid and its conjugates exceeds 99%.

The V_d of obeticholic acid is 618 L.

Obeticholic acid conjugates with glycine or taurine in the liver and is excreted in the bile.

The glycine and taurine conjugates of obeticholic acid are absorbed in the small intestine, leading to enterohepatic recirculation.

Conjugates can be deconjugated in the ileum and colon by the intestinal microbiota, leading to conversion back to obeticholic acid, which can be reabsorbed or excreted in the feces, which is the main route of elimination.

Following daily administration of obeticholic acid, accumulation of glycine and taurine conjugates of obeticholic acid occurred, which have in vitro pharmacological activity similar to the parent drug.

The metabolite-to-parent ratios for the glycine and taurine conjugates and obeticholic acid were 13.8 and 12.3, respectively, after daily administration.

A third additional metabolite of obeticholic acid, the 3-glucuronide, is formed but is considered to have minimal pharmacological activity.

After administration of radioactively labeled obeticholic acid, more than 87% is excreted in the feces.

Urinary excretion is less than 3%.

Indications

For the treatment of primary biliary cholangitis (PBC) in persons over 18 years of age: in combination with ursodeoxycholic acid (UDCA) – in patients with an inadequate therapeutic response to UDCA; as monotherapy – in patients intolerant to UDCA.

ICD codes

Dosage Regimen

Orally.

Patients taking bile acid binding resins should take obeticholic acid at the maximum possible interval – at least 4-6 hours before or 4-6 hours after taking the resin.

Before starting treatment with obeticholic acid, the patient’s liver condition must be assessed.

The presence of decompensated liver cirrhosis (Child-Pugh class B or C) or a history of decompensation in the patient must be ruled out before starting treatment, as Obeticholic acid is contraindicated in these patients.

The initial dose of obeticholic acid is 5 mg once daily for the first 6 months.

After the first 6 months, for patients who have not achieved an adequate reduction in alkaline phosphatase and/or total bilirubin levels and who tolerate the therapy well, the dose of obeticholic acid is increased to the maximum – 10 mg once daily.

Adverse Reactions

Endocrine system disorders common – thyroid dysfunction.

Nervous system disorders common – dizziness.

Cardiovascular system disorders common – palpitations.

Respiratory system disorders common – oropharyngeal pain.

Gastrointestinal system disorders very common – abdominal pain, discomfort; common – constipation.

Hepatobiliary disorders frequency unknown – hepatic failure, hyperbilirubinemia, jaundice, liver cirrhosis.

Skin and subcutaneous tissue disorders very common – pruritus; common – eczema, rash.

Musculoskeletal and connective tissue disorders common – arthralgia

General disorders and administration site conditions very common – fatigue; common – peripheral edema, fever.

Contraindications

Hypersensitivity to obeticholic acid; decompensated liver cirrhosis (e.g., Child-Pugh class B or C), including history; complete biliary obstruction.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Obeticholic acid is contraindicated in patients with decompensated liver cirrhosis (e.g., Child-Pugh class B or C), as well as in patients with a history of decompensation.

Use in Renal Impairment

Dosage adjustment is not required.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

There are limited data on elderly patients. No dose adjustment is required for elderly patients.

Special Precautions

After initiation of treatment, all patients should be under medical supervision to monitor the course of PBC (laboratory and clinical assessment methods should be used to determine the need for dosage regimen adjustment).

Patients at increased risk of developing liver failure should be monitored more closely with laboratory confirmation of worsening liver function and/or progression of cirrhosis.

Patients with progressive disease (e.g., from Child-Pugh class A to B or C) should have the frequency of administration of this agent reduced.

Cases of liver failure, sometimes fatal or leading to the need for liver transplantation, have been reported during treatment with obeticholic acid in patients with PBC with compensated or decompensated cirrhosis.

Some of these cases occurred in patients with decompensated liver cirrhosis when they were receiving treatment at a dose exceeding the recommended one for this patient population; however, cases of decompensation and liver failure continued to be reported in patients with decompensated cirrhosis, even when they received the recommended dose.

Patients taking obeticholic acid may experience increased ALT and AST activity, as well as clinical signs and symptoms of liver failure.

These signs usually appear within the first month of taking this agent.

Liver-related adverse events usually occur while taking obeticholic acid at doses above the maximum recommended 10 mg once daily.

All patients should be regularly monitored for the progression of PBC, including liver adverse reactions, using laboratory and clinical investigations to determine the need to discontinue treatment with obeticholic acid.

The course of the disease in patients at increased risk of hepatic decompensation, including those with elevated bilirubin, signs of portal hypertension (e.g., ascites, esophageal varices, persistent thrombocytopenia), concomitant liver diseases (e.g., autoimmune hepatitis, alcoholic liver disease) and/or severe intercurrent illnesses should be carefully monitored to determine the need to discontinue treatment with obeticholic acid.

Treatment with obeticholic acid in patients with laboratory or clinical signs of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), as well as with disease progression to Child-Pugh class B or C, should be permanently discontinued.

Treatment with obeticholic acid should be interrupted during severe intercurrent illness or in patients who experience clinically significant liver adverse reactions.

After resolution of the illness and in the absence of laboratory or clinical signs of hepatic decompensation, the potential risks and benefits of resuming treatment with obeticholic acid should be considered.

Effect on ability to drive and operate machinery

Obeticholic acid has no or negligible influence on the ability to drive and use machines.

Drug Interactions

INR decreases after simultaneous administration of warfarin and obeticholic acid.

INR should be monitored and the warfarin dose adjusted as necessary to maintain the target INR range when obeticholic acid and warfarin are used concomitantly.

Obeticholic acid may enhance the effect of concomitantly administered drugs that are substrates of CYP1A2.

Therapeutic monitoring of the effect of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended.

Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce the absorption of bile acids, which may reduce the effectiveness of obeticholic acid.

Patients taking these resins should take obeticholic acid at the maximum possible interval (at least 4-6 hours before or 4-6 hours after taking the resin).

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.