Urlyx/Urlyx 500

Urlyx: Urlyx 250 is a white to off-white powder encapsulated in an empty gelatin capsule size #0 with white cap and white body.
Each capsule contains: Ursodeoxycholic Acid, USP 250 mg.
Urlyx 500: White to off white colored caplet shaped film-coated tablets having break-line on one side and other side plain.
Each film-coated tablet contains: Ursodeoxycholic acid 500 mg.
Ursodeoxycholic acid, is a naturally occurring bile acid found in small quantities in normal human bile and in larger quantities in the biles of certain species of bears. It is a bitter-tasting white powder consisting of crystalline particles freely soluble in ethanol and glacial acetic acid, slightly soluble in chloroform, sparingly soluble in ether, and practically insoluble in water. The chemical name of Urlyx 500 is 3a,7β-dihydroxy-5β-cholan-24-oic (C₂₄H₄₀O₄). Urlyx 500 has a molecular weight of 392.56.

Pharmacology: Pharmacodynamics: Urlyx: Ursodeoxycholic acid is a product of metabolism of bacteria in the intestine. It is considered a secondary bile acid. The primary bile acids are produced hepatically and are stored in the gallbladder. It is released into the large intestine and is broken down into secondary bile acids by the bacteria present in the intestine. Both the primary and secondary bile acids assist in the metabolism of dietary fat. Ursodeoxycholic acid regulates cholesterol levels by slowing the rate at which the intestine is able to absorb cholesterol and to break down the micelles which contain cholesterol; this property of ursodeoxycholic acid is used in the non-surgical treatment of gallstones.
Urlyx 500: During chronic administration, Urlyx 500 becomes a major biliary and plasma bile acid. At a chronic dose of 13-15 mg/kg/day, Urlyx 500 constitutes 30-50% of biliary and plasma bile acids.
Mechanism of Action: Urlyx 500, a naturally occurring hydrophilic bile acid, derived from cholesterol, is present as a minor fraction of the total human bile acid pool. Oral administration of Urlyx 500 increases this fraction in a dose related manner, to become the major biliary acid, replacing/displacing toxic concentrations of endogenous hydrophobic bile acids that tend to accumulate in cholestatic liver disease.
Multiple mechanisms of action at the cellular and molecular level in addition to the replacement and displacement of toxic bile acids include cytoprotection of the injured bile duct epithelial cells (cholangiocytes) against toxic effects of bile acids, inhibition of apoptosis of hepatocytes, immunomodulatory effects via a number of mechanisms including decreasing expression of MHC class I proteins on hepatocytes and cholangiocytes, and stimulation of bile secretion by hepatocytes and cholangiocytes.
The cholesterol-lowering effect observed following the administration of Ursodeoxycholic acid in patients with primary biliary cirrhosis could be related to an improvement of cholestasis, modifications in cholesterol metabolism, or both. Changes in the endogenous bile acid composition induced by Ursodeoxycholic acid might be the common denominator of these two mechanisms.
Pharmacokinetics: Urlyx: Ursodeoxycholic acid is absorbed from the gastrointestinal tract and undergoes enterohepatic recycling. It is partly conjugated in the liver before being excreted into the bile. Under the influence of intestinal bacteria, the free and conjugated forms undergo 7a-dehydroxylation to lithocholic acid, some of which is excreted directly in the feces and the rest absorbed and mainly conjugated and sulfated by the liver before excretion in the feces. However, in comparison with chenodeoxycholic acid, less ursodeoxycholic acid undergoes such bacterial degradation.
Urlyx 500: Absorption: Urlyx 500 (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of Urlyx 500 is absorbed by passive diffusion and its absorption is incomplete.
Distribution: In healthy subjects, at least 70% of ursodeoxycholic acid (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated Urlyx 500 to plasma protein in healthy subjects or primary biliary cirrhosis (PBC) patients. However, since the efficacy of Urlyx 500 is related to its concentration in bile rather than in plasma, serum levels are not indicative of bioavailability in clinical settings. Its volume of distribution has not been determined, but is expected to be small since the drug is mostly distributed in the bile and small intestine. In bile, UDCA concentration reaches a peak in 1-3 hours.
Metabolism: Once absorbed, Urlyx 500 undergoes hepatic extraction to the extent of about 70% in the absence of liver disease. This leads to low blood levels in the systemic circulation. As the severity of liver disease increases, the extent of extraction decreases. In the liver, ursovis conjugated with glycine or taurine then secreted into bile. These conjugates of Urlyx 500 are absorbed in the small intestine by passive and active mechanisms. The conjugates can also be deconjugated in the ileum by intestinal enzymes, leading to the formation of free ursodiol that can be reabsorbed and reconjugated in the liver. Non absorbed Urlyx 500 passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some Urlyx 500 is epimerized to chenodiol (CDCA) via a 7-oxo intermediate. Chenodiol also undergoes 7-dehydroxylation to form lithocholic acid. These metabolites are poorly soluble and excreted in the feces. A small portion of lithocholic acid is reabsorbed, conjugated in the liver with glycine or taurine, and sulfated at the 3-position. The resulting sulfated lithocholic acid conjugates are excreted in bile and then lost in feces.
Lithocholic acid, when administered chronically to animals, causes cholestatic liver injury that may lead to death from liver failure in certain species unable to form sulfate conjugates. Urlyx 500 is 7-dehydroxylated more slowly, than chenodiol. For equimolar doses of Urlyx 500 and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during Urlyx 500 administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with Urlyx 500 therapy, a reduced capacity to sulfate may exist in some individuals. Nonetheless, such a deficiency has not yet been clearly demonstrated and must be extremely rare, given the several thousand patient-years of clinical experience with Urlyx 500.
Excretion: Ursodeoxycholic Acid is excreted primarily in the feces with treatment urinary excretion increases but remains less than 1%, except in severe cholestatic liver disease.

Urlyx: Ursodeoxycholic acid suppresses the synthesis and secretion of cholesterol by the liver and inhibits intestinal absorption of cholesterol. It is used for the dissolution of cholesterol-rich gallstones in patients with functioning gallbladders.
Urlyx 500: Urlyx 500, also known as ursodeoxycholic acid (UDCA) is indicated for: the management of cholestatic liver diseases, such as primary biliary cirrhosis (PBC).
Cholestatic liver diseases are characterized by a decrease in bile secretion and bile flow. Caution has to be exercised to maintain the bile flow of the patients taking UDCA.
The diagnosis of cholestatic liver diseases is based on the biochemical signs of cholestasis (such as an increase in alkaline phosphatase, γ-GT, bilirubin), and also an increase in IgM levels and the presence of antimitochondrial antibodies in PBC.
The monitoring of Ursodeoxycholic Acid in the management of cholestatic liver diseases should be based on the biochemical parameters of cholestasis, as described as previously mentioned, as well as on signs of hepatic cytolysis (such as AST, ALT) which are very often associated with cholestasis during the progression of the diseases.
Serum liver function tests (γ-GT, alkaline phosphatase, AST, ALT) and bilirubin level should be monitored every month for three months after start of therapy, and every six months thereafter. Improved serum liver function tests (e.g. AST, ALT) do not always correlate with improved disease status. In addition to identifying responsive and non-responsive patients, this monitoring will allow the early detection of a possible deterioration of the hepatic function. For patients who have a recent history of adequate biochemical response to the treatment, UDCA discontinuation should be considered when serum liver function tests increase to a level considered clinically significant, generally increase in ALT, AST levels three times the baseline value and increase in total bilirubin to twice the baseline value, confirmed by repeated tests.
Ursodeoxycholic acid is not indicated for the treatment of decompensated cirrhosis.
Geriatrics: Appropriate studies with Ursodeoxycholic acid have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of Ursodeoxycholic acid in the elderly are not expected.
Pediatrics: The safety and effectiveness of Ursodeoxycholic acid in children have not been established.

Urlyx: Initial dose of 1 capsule every 8 hours or as prescribed by the physician.
Urlyx 500: Recommended Dose: The recommended adult dosage for Ursodeoxycholic acid in the treatment of PBC is 13-15 mg/kg/day administered in two to four divided doses with food. The Ursodeoxycholic acid, 500 mg scored tablet can be broken in halves to provide recommended dosage.
Dosing Considerations: Patient Monitoring: Serum liver function tests (γ-GT, alkaline phosphatase, AST, ALT) and bilirubin level should be monitored every month for three months after start of therapy, and every six months thereafter. Serial monitoring will allow for the early detection of a possible deterioration of the hepatic function. Serum levels of these parameters usually decrease rapidly. Improved serum liver tests (e.g. AST, ALT) do not always correlate with improved disease status. For patients who have a recent history of adequate biochemical response to the treatment, UDCA discontinuation should be considered when serum liver function tests increase to a level considered clinically.
Caution has to be exercised to maintain the bile flow of the patients taking UDCA.

Urlyx: There have been no reports on ursodeoxycholic acid overdosage.
Urlyx 500: Accidental or intentional overdosage with ursodeoxycholic acid has not been reported. The most likely manifestation of severe overdose with ursodeoxycholic acid would probably be diarrhea, which should be treated symptomatically.
Symptoms of acute toxicity were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters.

Urlyx: Complete atresia of bile duct, radiopaque calcified gallstones, non-functional gallbladder, acute cholecystitis.
Urlyx 500: Ursodeoxycholic acid is contraindicated in: patients with complete biliary obstruction of extrahepatic origin; patients with widespread intrahepatic obstruction and patients who are hypersensitive to Urlyx 500 or to any ingredient in the formulation for a complete listing.

Urlyx: Ursodeoxycholic acid should not be given to patients with intestinal and hepatic disorder that interfere with enterohepatic circulation of bile salts. It is ineffective for the dissolution of calcified and pigmented gallstones and is of no value in patients without a patent and a functioning gallbladder. Licensed product information recommends that its use should be avoided in pregnancy.
Urlyx 500: Carcinogenesis and Mutagenesis: Ursodeoxycholic acid have no carcinogenic, mutagenic or teratogenic effects in laboratory animals treated at higher doses than those intended for therapy in humans, and after long-term treatment.
Hepatic/Biliary/Pancreatic: Patients with visceral bleeding, hepatic encephalopathy ascites, or in need of an urgent liver transplant, should receive appropriate specific treatment. Caution should be exercised when UDCA is administered in a setting of partial biliary obstruction of extra-hepatic origin.
Monitoring and Laboratory Tests: Lithocholic acid, one of the metabolites of Ursodeoxycholic acid is hepatotoxic unless it is effectively detoxified in the liver.
Therefore, the following tests are important for patient monitoring: three months after start of therapy, and every six months thereafter. Serial monitoring will allow for the early detection of a possible deterioration of the hepatic function. Serum levels of these parameters usually decrease rapidly. Improved of adequate biochemical response to the treatment, UDCA discontinuation should be considered when serum liver function tests increase to a level considered clinically significant.
Caution has to be exercised to maintain the bile flow of the patients taking UDCA.
Use in Pregnancy: There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Ursodeoxycholic acid should not be used in women who are or may become pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Use in Lactation: It is not known whether Urlyx 500 is excreted in human milk. Since many drugs are excreted in human milk, caution should be exercised when Ursodeoxycholic acid is administered to a nursing mother.
Use in Children: The safety and effectiveness of Ursodeoxycholic acid in children have not been established.
Use in the Elderly: Appropriate studies with Ursodeoxycholic acid have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of Ursodeoxycholic acid in the elderly are not expected.

Urlyx: Pregnancy: Pregnancy Category B: There are no adequate or well-controlled studies in pregnant women. The drug should be used during pregnancy only if clearly needed.
Lactation: It is not known whether ursodeoxycholic acid is excreted in human milk. Caution should be exercised when it is administered to a lactating mother.
Urlyx 500: Animal studies did not show an influence of UDCA on fertility. Human data on fertility effects following treatment with UDCA are not available.
Pregnancy: There are no or limited amounts of data from the use of UDCA in pregnant women. Studies in animals have shown reproductive toxicity during the early phase gestation. Ursodeoxycholic acid capsules must not be used during pregnancy unless clearly necessary.
Women of childbearing potential: Women of childbearing potential should be treated only if they use reliable contraception: non-hormonal contraceptives or low-oestrogen oral contraceptives are recommended. However, in patients taking Ursodeoxycholic acid for dissolution of gallstones, effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis. The possibility of a pregnancy must be excluded before beginning treatment.
Breastfeeding: According to few documented cases of breastfeeding women, milk levels of UDCA are very low and probably no adverse reactions are to be expected in breastfed infants.

Urlyx: Ursodeoxycholic acid may cause nausea, vomiting, and other gastrointestinal disturbances; diarrhea is reported to occur less frequently than with chenodeoxycholic acid. Increased liver enzyme value is also less likely. Pruritus may occur. Treatment with ursodeoxycholic acid may cause more calcification of cholesterol stones than chenodeoxycholic acid.
Urlyx 500: The following adverse reactions have been reported during clinical trials and are ranked using the following frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Gastrointestinal disorders: In clinical studies, reports of pasty stools or diarrhoea during treatment with ursodeoxycholic acid were common.
In very rare cases, severe right upper abdominal pain has occurred during the treatment of primary biliary cholangitis.
Hepatobiliary disorders: During treatment with ursodeoxycholic acid calcification of gallstones can occur in very rare cases.
During the treatment of advanced stages of primary biliary cholangitis decompensation of cirrhosis has been observed in very rare cases, which partially regressed after treatment discontinuation.
Hypersensitivity reactions: Very rarely urticaria may occur.

Urlyx: Ursodeoxycholic acid should not be used with drugs that increase bile cholesterol such as estrogenic hormones and cholesterol-lowering drug such as clofibrate. Use with bile-acid binding drugs including antacids, charcoal, and cholestyramine should be avoided since this may reduce the effectiveness of therapy with ursodeoxycholic acid.
Urlyx 500: Ursodeoxycholic acid should not be administered concomitantly with colestyramine, colestipol or antacids containing aluminum hydroxide and/or smectite (aluminum oxide), because these preparations bind ursodeoxycholic acid in the intestine and thereby inhibit absorption and efficacy. Should the use of a preparation containing one of these substances be necessary, it must be taken at least 2 hours before or after Ursodeoxycholic acid. Ursodeoxycholic acid can affect the absorption of ciclosporin from the intestine. In patients receiving ciclosporin treatment, blood concentrations of this substance should therefore be checked by the physician and the ciclosporin dose adjusted if necessary. Due to the effect of UDCA on the secretion of bile acids there is a theoretical possibility that the absorption of other lipophilic substances could be affected. In certain rare cases Ursodeoxycholic acid can reduce the absorption of ciprofloxacin. Ursodeoxycholic acid has been shown to reduce the plasma peak concentrations Cmax nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and UDCA is recommended. An increase of dose may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These two interactions in addition to shown in vitro interaction could be explained by enzyme induction with CYP3A4. However, no induction was observed in a well-designed interaction study with budesonide. Oestrogenic hormones and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may encourage biliary lithiasis, which is a counter-effect to ursodeoxycholic acid used for dissolution of gallstones. A clinical study on healthy volunteers with concomitant use of UDCA (500 mg/day) and rosuvastatin. The clinical relevance of this interaction and even the interactions concerning other statins are unknown.

Store at temperatures not exceeding 30°C.

Cholagogues, Cholelitholytics & Hepatic Protectors

A05AA02 - ursodeoxycholic acid ; Belongs to the class of bile acids. Used in bile therapy.

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