ACTIGALL

July 2, 2001

Ursodeoxycholic Acid, UrsodiolActigall®

ACTIGALL CAPSULES(CAP 300 MG )

Description: Ursodeoxycholic acid, ursodiol is an oral, naturally occurring bile acid agent. Unlike chenodiol, a bile acid no longer used in the US, ursodiol is not associated with hepatotoxicity. Ursodiol is primarily used to solubilize radiolucent (cholesterol) gallstones. Gallstone dissolution requires months of therapy, and complete dissolution may not occur in all patients. The drug helps prevent gallstones during rapid weight loss. Ursodiol is used as an adjunct in treating cholestatic hepatobiliary diseases in adults, children; many of these uses are "off-label" indications. In these hepatobiliary disorders, ursodiol reduces cholestasis, pruritus, and elevated hepatic enzymes, but slowing of disease progression to cirrhosis is not always evident. Actigall® was originally approved by the FDA in 1987 for gallstone dissolution and was subsequently approved for preventing gallstones in obese patients during rapid weight-loss diets in 1997. Ursodiol (Urso®) was approved for the treatment of primary biliary cirrhosis (PBC) in December 1997, and is designated an orphan drug for this indication. In 2000, a biliary lithotripsy device was FDA-approved for use along with Actigall® for selected patients with a solitary radiolucent gallstone ranging 4—20 mm in diameter.

Mechanism of Action: Ursodiol's therapeutic sites of action are in the liver, bile, and gut lumen. At chronic doses of 13—15 mg/kg/day, ursodiol constitutes roughly 30—50% of the total biliary and plasma bile acids. •Mechanism of gallstone dissolution: Ursodiol decreases the cholesterol content of bile and associated gallstones by reducing the hepatic synthesis and secretion of cholesterol and the fractional reabsorption of cholesterol by the intestine. Ursodiol does not inhibit the synthesis and secretion of endogenous bile acids or phospholipids into the bile. In addition to solubilizing cholesterol in micelles, ursodiol causes dispersion of cholesterol as liquid crystals in aqueous media. The actions of ursodiol change the nature of the bile from cholesterol-precipitating to cholesterol-solubilizing, thus resulting in an environment conducive to gallstone dissolution. •Mechanism in primary biliary cirrhosis (PBC) and other cholestatic liver diseases: Retardation of disease progression has only been noted in clinical trials for PBC; further investigation is needed to prove ursodiol retards the progression to cirrhosis in other cholestatic liver diseases. Ursodiol's benefit to date in other hepatic diseases has been a reduction in LFTs and clinical symptoms (e.g., pruritus). The exact mechanism by which ursodiol retards progression of liver disease in patients with primary biliary cirrhosis is still unclear. Retention of high concentrations of hydrophobic bile acids within hepatocytes during cholestasis has been shown to damage the membranes of intracellular organelles. Improved hepatic bile flow, decreased bile viscosity, reduced ductular proliferation and reduced portal inflammation appear to be important effects of ursodiol. Ursodiol has been shown to reduce the intrahepatic concentration of hydrophobic bile acids within hepatocytes, and to increase the hydrophilicity of the bile acid pool.[3015] Ursodiol also interferes with the enterohepatic circulation of bile acids by inhibiting reuptake of endogenous bile acids in the terminal ileum. Studies have suggested that ursodiol may have an immunomodulatory effect and inhibit the production of certain cytotoxic cytokines, which may reduce lipid peroxidation in hepatocytes.[3016]

Pharmacokinetics: Ursodiol is administered orally. Following oral administration, ursodiol is absorbed via passive diffusion. Roughly 90% of a therapeutic dose is absorbed in the small intestine, after which it enters the portal vein and is extracted from the portal blood by the liver. In the liver, ursodiol is conjugated with either glycine or taurine, then is secreted into the hepatic bile ducts. Ursodiol is then concentrated into the bile in the gallbladder. Ursodiol and the other bile acids are expelled into the duodenum via the cystic and common bile ducts by gallbladder contractions induced by the physiologic response to oral ingestion of food. Only small amounts of ursodiol appear in the systemic circulation and very small amounts are excreted into the urine. With repeated dosing, bile ursodiol concentrations reach a steady-state in about 3 weeks; ursodiol concentrations in the bile do not exceed 60% of the total bile acid pool. After ursodiol is discontinued, the concentration of the drug in bile falls exponentially, declining to roughly 5—10% of its steady-state level within 1 week.

Beyond conjugation, ursodiol is not catabolized appreciably by the liver or intestinal mucosa. A small proportion of the orally administered drug undergoes bacterial degradation in the intestine with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, the conjugated glyco- or tauro-ursodiol may be deconjugated in the small bowel, yielding free ursodiol. All of these bacterial degradation products are relatively insoluble and large proportions of these products are excreted in the feces. Some free ursodiol is reabsorbed and reconjugated by the liver. Eighty-percent of the lithocholic acid formed in the small bowel is excreted in the feces, but 20% is reabsorbed and then sulfated by the liver to lithocholyl conjugates excreted in the bile and lost in the feces. Small amounts of 7-keto-lithocholic acid are reabsorbed and stereospecifically reduced by the liver to chenodiol.

•Special Populations: No dosage reductions appear needed in hepatic or renal dysfunction. Pediatric clinical experience to date suggests no relevant pharmacokinetic issues when compared to adults. Lithocholic acid, when administered chronically to animals, causes serious liver injury in certain animal species unable to form sulfate conjugates. However, humans can readily sulfate lithocholic acid. Ursodiol is 7-dehydroxylated to lithocholic acid more slowly than chenodiol, and steady-state levels of lithocholic acid in biliary bile acids are lower during ursodiol treatment than with the use of chenodiol. While a reduced capacity to sulfate lithocholic acid may exist in some individuals, such a deficiency has not yet been clearly demonstrated and must be extremely rare. Liver injury has not been associated with ursodiol therapy in widespread clinical use.

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July 5, 2001

I didn't think PSCers could go without that

until least after tx.

Beverly

I am another PSC'er who doesn't take the actigall. I stopped it on my own. I had a procedure done while having my ERCP. The DR opened up the narrowing like they do with heart patients. (angioplasty)

Every since then I haven't had any abnormal blood test. My scan's and X-rays and every other test has come back fine. My doctor told me that was fine to stop it BUT as soon as my liver enzymes were elevated back to the actigal I go.

I don't think but I am not a doctor : ) That a person should be committed to a medicine if their body is handling the load on it's own. I think we all have to remember everyone is different and will re act to the disease differently. Some will progress a lot faster than others. Some will not be asymptomatic while others could be the poster child for PSC with all the symptoms.

Other than I catch a cold flu or virus like my name is written on everyone that I pass. I have a few problems that maybe related to the PSC or not. There hasn't been enough research to know yet. I have been without symptoms of PSC for one year.

Tricia dx'd 08/99

July 5, 2001

Tricia - there are strong indications that Urso/Actigall has a preventive

effect for cholangiocarcinoma in PSC patients, which is why many of us

continue to take it. PSCers have a strong tendency towards the cancer.

Also, the disease WILL progress, albeit more slowly in some than others. I

also went a year after diagnosis without symptoms; I've also had my common

bile duct dilated.

I too appear to have a slowly progressing case (knock on wood). Since there

are no systemic side-effects, I'll keep taking it (my LFTs are normal).

It's basically a synthetic version of something your body already makes.

My PSC is so far limited to the common bile duct, but there are visible (via

ERCP) changes in the intrahepatic ducts. The problem is, asymptomatic isn't

good enough. Cholangiocarcinoma does not currently have a good dianostic

test Almost everyone agrees that the CA-19 test is better than nothing, but

not by much. By the time you do show symptoms, you may be in deep trouble.

To stop taking it is just not worth the risk to me (and Judy would have a

fit if I did).

Arne

50 - UC 1977 - PSC 2000

Alive and (mostly) well in Minneasota

.... I am another PSC'er who doesn't take the actigall. I stopped it on my

own. I

had a procedure done while having my ERCP. The DR opened up the narrowing

like they do with heart patients. (angioplasty)

Every since then I haven't had any abnormal blood test. My scan's and X-rays

and every other test has come back fine. My doctor told me that was fine to

stop it BUT as soon as my liver enzymes were elevated back to the actigal I

go.

.... That a person should be committed to

a medicine if their body is handling the load on it's own.

July 5, 2001