NDC 0023-6145 Actigall

Ursodiol

NDC Product Code 0023-6145

NDC Code: 0023-6145

Proprietary Name: Actigall What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Ursodiol What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Product Characteristics

Color(s):
PINK (C48328)
WHITE (C48325)
Shape: CAPSULE (C48336)
Size(s):
22 MM
Imprint(s):
ACTIGALL;300;MG
Score: 1

NDC Code Structure

NDC 0023-6145-01

Package Description: 100 CAPSULE in 1 BOTTLE

NDC Product Information

Actigall with NDC 0023-6145 is a a human prescription drug product labeled by Allergan, Inc.. The generic name of Actigall is ursodiol. The product's dosage form is capsule and is administered via oral form.

Labeler Name: Allergan, Inc.

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Actigall Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • URSODIOL 300 mg/1

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Bile Acid - [EPC] (Established Pharmacologic Class)
  • Bile Acids and Salts - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Allergan, Inc.
Labeler Code: 0023
FDA Application Number: NDA019594 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 12-31-1987 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2019 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

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Actigall Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Description

Actigall is a bile acid available as 300 mg capsules suitable for oral administration.Actigall is ursodiol, USP (ursodeoxycholic acid), a naturally occurring bile acid found in small quantities in normal human bile and in the biles of certain other mammals. It is a bitter-tasting, white powder freely soluble in ethanol, methanol, and glacial acetic acid; sparingly soluble in chloroform; slightly soluble in ether; and insoluble in water. The chemical name for ursodiol is 3α,7β-Dihydroxy-5β-cholan-24-oic acid (C24H40O4). Ursodiol, USP has a molecular weight of 392.57. Its structure is shown below:Inactive Ingredients: Colloidal silicon dioxide, magnesium stearate, and starch (corn). Gelatin capsules contain ferric oxide, gelatin, and titanium dioxide. The capsules are printed with edible ink containing black iron oxide.

Clinical Pharmacology

About 90% of a therapeutic dose of Actigall is absorbed in the small bowel after oral administration. After absorption, ursodiol enters the portal vein and undergoes efficient extraction from portal blood by the liver (i.e., there is a large “first-pass” effect) where it is conjugated with either glycine or taurine and is then secreted into the hepatic bile ducts. Ursodiol in bile is concentrated in the gallbladder and expelled into the duodenum in gallbladder bile via the cystic and common ducts by gallbladder contractions provoked by physiologic responses to eating. Only small quantities of ursodiol appear in the systemic circulation and very small amounts are excreted into urine. The sites of the drug’s therapeutic actions are in the liver, bile, and gut lumen.Beyond conjugation, ursodiol is not altered or catabolized appreciably by the liver or intestinal mucosa. A small proportion of orally administered drug undergoes bacterial degradation with each cycle of enterohepatic circulation. Ursodiol can be both oxidized and reduced at the 7-carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Further, there is some bacterially catalyzed deconjugation of glyco- and tauro-ursodeoxycholic acid in the small bowel. Free ursodiol, 7-keto-lithocholic acid, and lithocholic acid are relatively insoluble in aqueous media and larger proportions of these compounds are lost from the distal gut into the feces. Reabsorbed free ursodiol is reconjugated by the liver. Eighty percent of lithocholic acid formed in the small bowel is excreted in the feces, but the 20% that is absorbed is sulfated at the 3-hydroxyl group in the liver to relatively insoluble lithocholyl conjugates which are excreted into bile and lost in feces. Absorbed 7-keto-lithocholic acid is stereospecifically reduced in the liver to chenodiol.Lithocholic acid causes cholestatic liver injury and can cause death from liver failure in certain species unable to form sulfate conjugates. Lithocholic acid is formed by 7-dehydroxylation of the dihydroxy bile acids (ursodiol and chenodiol) in the gut lumen. The 7-dehydroxylation reaction appears to be alpha-specific, i.e., chenodiol is more efficiently 7-dehydroxylated than ursodiol and, for equimolar doses of ursodiol and chenodiol, levels of lithocholic acid appearing in bile are lower with the former. Man has the capacity to sulfate lithocholic acid. Although liver injury has not been associated with ursodiol therapy, a reduced capacity to sulfate may exist in some individuals, but such a deficiency has not yet been clearly demonstrated.

Pharmacodynamics

Ursodiol suppresses hepatic synthesis and secretion of cholesterol, and also inhibits intestinal absorption of cholesterol. It appears to have little inhibitory effect on synthesis and secretion into bile of endogenous bile acids, and does not appear to affect secretion of phospholipids into bile.With repeated dosing, bile ursodeoxycholic acid concentrations reach a steady-state in about 3 weeks. Although insoluble in aqueous media, cholesterol can be solubilized in at least two different ways in the presence of dihydroxy bile acids. In addition to solubilizing cholesterol in micelles, ursodiol acts by an apparently unique mechanism to cause dispersion of cholesterol as liquid crystals in aqueous media. Thus, even though administration of high doses (e.g., 15 - 18 mg/kg/day) does not result in a concentration of ursodiol higher than 60% of the total bile acid pool, ursodiol-rich bile effectively solubilizes cholesterol. The overall effect of ursodiol is to increase the concentration level at which saturation of cholesterol occurs.The various actions of ursodiol combine to change the bile of patients with gallstones from cholesterol-precipitating to cholesterol-solubilizing, thus resulting in bile conducive to cholesterol stone dissolution.After ursodiol dosing is stopped, the concentration of the bile acid in bile falls exponentially, declining to about 5 to 10% of its steady-state level in about 1 week.

Clinical Results

Gallstone DissolutionOn the basis of clinical trial results in a total of 868 patients with radiolucent gallstones treated in 8 studies (three in the U.S. involving 282 patients, one in the U.K. involving 130 patients, and four in Italy involving 456 patients) for periods ranging from 6 to 78 months with Actigall doses ranging from about 5 - 20 mg/kg/day, an Actigall dose of about 8 - 10 mg/kg/day appeared to be the best dose. With an Actigall dose of about 10 mg/kg/day, complete stone dissolution can be anticipated in about 30% of unselected patients with uncalcified gallstones < 20 mm in maximal diameter treated for up to 2 years. Patients with calcified gallstones prior to treatment, or patients who develop stone calcification or gallbladder nonvisualization on treatment, and patients with stones > 20 mm in maximal diameter rarely dissolve their stones. The chance of gallstone dissolution is increased up to 50% in patients with floating or floatable stones (i.e., those with high cholesterol content), and is inversely related to stone size for those < 20 mm in maximal diameter. Complete dissolution was observed in 81% of patients with stones up to 5 mm in diameter. Age, sex, weight, degree of obesity, and serum cholesterol level are not related to the chance of stone dissolution with Actigall.A nonvisualizing gallbladder by oral cholecystogram prior to the initiation of therapy is not a contraindication to Actigall therapy (the group of patients with nonvisualizing gallbladders in the Actigall studies had complete stone dissolution rates similar to the group of patients with visualizing gallbladders). However, gallbladder nonvisualization developing during ursodiol treatment predicts failure of complete stone dissolution and in such cases therapy should be discontinued.Partial stone dissolution occurring within 6 months of beginning therapy with Actigall appears to be associated with a > 70% chance of eventual complete stone dissolution with further treatment; partial dissolution observed within 1 year of starting therapy indicates a 40% probability of complete dissolution.Stone recurrence after dissolution with Actigall therapy was seen within 2 years in 8/27 (30%) of patients in the U.K. studies. Of 16 patients in the U.K. study whose stones had previously dissolved on chenodiol but later recurred, 11 had complete dissolution on Actigall. Stone recurrence has been observed in up to 50% of patients within 5 years of complete stone dissolution on ursodiol therapy. Serial ultrasonographic examinations should be obtained to monitor for recurrence of stones, bearing in mind that radiolucency of the stones should be established before another course of Actigall is instituted. A prophylactic dose of Actigall has not been established.Gallstone PreventionTwo placebo-controlled, multicenter, double-blind, randomized, parallel group trials in a total of 1,316 obese patients were undertaken to evaluate Actigall in the prevention of gallstone formation in obese patients undergoing rapid weight loss. The first trial consisted of 1,004 obese patients with a body mass index (BMI) ≥ 38 who underwent weight loss induced by means of a very low calorie diet for a period of 16 weeks. An intent-to-treat analysis of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 600, or 1200 mg/day of Actigall experienced a 6%, 3%, and 2% incidence of gallstone formation, respectively. The mean weight loss for this 16-week trial was 47 lb for the placebo group, and 47, 48, and 50 lb for the 300, 600, and 1200 mg/day Actigall groups, respectively.The second trial consisted of 312 obese patients (BMI ≥ 40) who underwent rapid weight loss through gastric bypass surgery. The trial drug treatment period was for 6 months following this surgery. Results of this trial showed that gallstone formation occurred in 23% of the placebo group, while those patients on 300, 600, or 1200 mg/day of Actigall experienced a 9%, 1%, and 5% incidence of gallstone formation, respectively. The mean weight loss for this 6-month trial was 64 lb for the placebo group, and 67, 74, and 72 lb for the 300, 600, and 1200 mg/day Actigall groups, respectively.

Watchful Waiting

Watchful waiting has the advantage that no therapy may ever be required. For patients with silent or minimally symptomatic stones, the rate of development of moderate-to-severe symptoms or gallstone complications is estimated to be between 2% and 6% per year, leading to a cumulative rate of 7 to 27% in 5 years. Presumably the rate is higher for patients already having symptoms.

Cholecystectomy

For patients with symptomatic gallstones, surgery offers the advantage of immediate and permanent stone removal, but carries a high risk in some patients. About 5% of cholecystectomized patients have residual symptoms or retained common duct stones. The spectrum of surgical risk varies as a function of age and the presence of disease other than cholelithiasis.Mortality Rates for Cholecystectomy in the U.S. (National Halothane Study, JAMA 1966; 197:775-8) 27,600 Cholecystectomies (Smoothed Rates) Deaths/1000 Operations***Age (Yrs)      Cholecystectomy      Cholecystectomy + Common Duct ExplorationLow Risk Patients*        Women0 - 49.542.13 50 - 692.8010.10            Men0 - 491.044.12 50 - 695.4119.23    High Risk Patients**           Women0 - 4912.6647.62 50 - 6917.2458.82            Men0 - 4924.3990.91 50 - 6933.33111.11 * In good health or with moderate systemic disease.** With severe or extreme systemic disease.*** Includes both elective and emergency surgery.Women in good health or who have only moderate systemic disease and are under 49 years of age have the lowest surgical mortality rate (0.054); men in all categories have a surgical mortality rate twice that of women. Common duct exploration quadruples the rates in all categories. The rates rise with each decade of life and increase tenfold or more in all categories with severe or extreme systemic disease.

Indications And Usage

  • Actigall is indicated for patients with radiolucent, noncalcified gallbladder stones < 20 mm in greatest diameter in whom elective cholecystectomy would be undertaken except for the presence of increased surgical risk due to systemic disease, advanced age, idiosyncratic reaction to general anesthesia, or for those patients who refuse surgery. Safety of use of Actigall beyond 24 months is not established.Actigall is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

Contraindications

  • Actigall will not dissolve calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment  stones. Hence, patients with such stones are not candidates for Actigall therapy.Patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-gastrointestinal fistula are not candidates for Actigall therapy.Allergy to bile acids.

Liver Tests

Ursodiol therapy has not been associated with liver damage. Lithocholic acid, a naturally occurring bile acid, is known to be a liver-toxic metabolite. This bile acid is formed in the gut from ursodiol less efficiently and in smaller amounts than that seen from chenodiol. Lithocholic acid is detoxified in the liver by sulfation and, although man appears to be an efficient sulfater, it is possible that some patients may have a congenital or acquired deficiency in sulfation, thereby predisposing them to lithocholate-induced liver damage.Abnormalities in liver enzymes have not been associated with Actigall therapy and, in fact, Actigall has been shown to decrease liver enzyme levels in liver disease. However, patients given Actigall should have SGOT (AST) and SGPT (ALT) measured at the initiation of therapy and thereafter as indicated by the particular clinical circumstances.

Drug Interactions

Bile acid sequestering agents such as cholestyramine and colestipol may interfere with the action of Actigall by reducing its absorption. Aluminum-based antacids have been shown to adsorb bile acids in vitro and may be expected to interfere with Actigall in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and clofibrate (and perhaps other lipid-lowering drugs) increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may counteract the effectiveness of Actigall.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Ursodeoxycholic acid was tested in 2-year oral carcinogenicity studies in CD-1 mice and Sprague-Dawley rats at daily doses of 50, 250, and 1000 mg/kg/day. It was not tumorigenic in mice. In the rat study, it produced statistically significant dose-related increased incidences of pheochromocytomas of adrenal medulla in males (p = 0.014, Peto trend test) and females (p = 0.004, Peto trend test). A 78-week rat study employing intrarectal instillation of lithocholic acid and tauro-deoxycholic acid, metabolites of ursodiol and chenodiol, has been conducted. These bile acids alone did not produce any tumors. A tumor-promoting effect of both metabolites was observed when they were co-administered with a carcinogenic agent. Results of epidemiologic studies suggest that bile acids might be involved in the pathogenesis of human colon cancer in patients who had undergone a cholecystectomy, but direct evidence is lacking. Ursodiol is not mutagenic in the Ames test. Dietary administration of lithocholic acid to chickens is reported to cause hepatic adenomatous hyperplasia.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits with ursodiol doses up to 200-fold the therapeutic dose and have revealed no evidence of impaired fertility or harm to the fetus at doses of 20- to 100-fold the human dose in rats and at 5-fold the human dose (highest dose tested) in rabbits. Studies employing 100- to 200-fold the human dose in rats have shown some reduction in fertility rate and litter size. There have been no adequate and well-controlled studies of the use of ursodiol in pregnant women, but inadvertent exposure of 4 women to therapeutic doses of the drug in the first trimester of pregnancy during the Actigall trials led to no evidence of effects on the fetus or newborn baby. Although it seems unlikely, the possibility that ursodiol can cause fetal harm cannot be ruled out; hence, the drug is not recommended for use during pregnancy.

Nursing Mothers

It is not known whether ursodiol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Actigall is administered to a nursing mother.

Pediatric Use

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

Geriatric Use

In worldwide clinical studies of Actigall, approximately 14% of subjects were over 65 years of age (approximately 3% were over 75 years old). In a subgroup analysis of existing clinical trials, patients greater than 56 years of age did not exhibit statistically significantly different complete dissolution rates from the younger population. No age-related differences in safety and effectiveness were found. Other reported clinical experience has not identified differences in response in elderly and younger patients. However, small differences in efficacy and greater sensitivity of some elderly individuals taking Actigall cannot be ruled out. Therefore, it is recommended that dosing proceed with caution in this population.

Adverse Reactions

The nature and frequency of adverse experiences were similar across all groups.The following tables provide comprehensive listings of the adverse experiences reported that occurred with a 5% incidence level: GALLSTONE DISSOLUTION  Ursodiol Placebo 8 - 10 mg/kg/day(N = 155) (N = 159)  N (%) N (%) Body as a Whole        Allergy 8 (5.2) 7 (4.4)    Chest Pain 5 (3.2) 10 (6.3)    Fatigue 7 (4.5) 8 (5.0)    Infection Viral 30 (19.4) 41 (25.8) Digestive System        Abdominal Pain 67 (43.2) 70 (44.0)    Cholecystitis 8 (5.2) 7 (4.4)    Constipation 15 (9.7) 14 (8.8)    Diarrhea 42 (27.1) 34 (21.4)    Dyspepsia 26 (16.8) 18 (11.3)    Flatulence 12 (7.7) 12 (7.5)    Gastrointestinal Disorder 6 (3.9) 8 (5.0)    Nausea 22 (14.2) 27 (17.0)    Vomiting 15 (9.7) 11 (6.9) Musculoskeletal System        Arthralgia 12 (7.7) 24 (15.1)    Arthritis 9 (5.8) 4 (2.5)    Back Pain 11 (7.1) 18 (11.3)    Myalgia 9 (5.8) 9 (5.7) Nervous System        Headache 28 (18.1) 34 (21.4)    Insomnia 3 (1.9) 8 (5.0) Respiratory System        Bronchitis 10 (6.5) 6 (3.8)    Coughing 11 (7.1) 7 (4.4)    Pharyngitis 13 (8.4) 5 (3.1)    Rhinitis 8 (5.2) 11 (6.9)    Sinusitis 17 (11.0) 18 (11.3)    Upper Respiratory        Tract Infection 24 (15.5) 21 (13.2) Urogenital System        Urinary Tract Infection 10 (6.5) 7 (4.4) GALLSTONE PREVENTION  Actigall Placebo 600 mg (N = 322) (N = 325) N (%) N (%) Body as a Whole        Fatigue 25 (7.8) 33 (10.2)    Infection Viral 29 (9.0) 29 (8.9)    Influenza-like Symptoms 21 (6.5) 19 (5.8) Digestive System        Abdominal Pain 20 (6.2) 39 (12.0)    Constipation 85 (26.4) 72 (22.2)    Diarrhea 81 (25.2) 68 (20.9)    Flatulence 15 (4.7) 24 (7.4)    Nausea 56 (17.4) 43 (13.2)    Vomiting 44 (13.7) 44 (13.5) Musculoskeletal System        Back Pain 38 (11.8) 21 (6.5)    Musculoskeletal Pain 19 (5.9) 15 (4.6) Nervous System        Dizziness 53 (16.5) 42 (12.9)    Headache 80 (24.8) 78 (24.0) Respiratory System        Pharyngitis 10 (3.1) 19 (5.8)    Sinusitis 17 (5.3) 18 (5.5)    Upper Respiratory        Tract Infection 40 (12.4) 35 (10.8) Skin and Appendages        Alopecia 17 (5.3) 8 (2.5) Urogenital System        Dysmenorrhea 18 (5.6) 19 (5.8)

Overdosage

Neither accidental nor intentional overdosing with Actigall has been reported. Doses of Actigall in the range of 16 - 20 mg/kg/day have been tolerated for 6 to 37 months without symptoms by 7 patients. The LD50 for ursodiol in rats is over 5000 mg/kg given over 7 to 10 days and over 7500 mg/kg for mice. The most likely manifestation of severe overdose with Actigall would probably be diarrhea, which should be treated symptomatically.

Gallstone Dissolution

The recommended dose for Actigall treatment of radiolucent gallbladder stones is 8 - 10 mg/kg/day given in 2 or 3 divided doses.Ultrasound images of the gallbladder should be obtained at 6-month intervals for the first year of Actigall therapy to monitor gallstone response. If gallstones appear to have dissolved, Actigall therapy should be continued and dissolution confirmed on a repeat ultrasound examination within 1 to 3 months. Most patients who eventually achieve complete stone dissolution will show partial or complete dissolution at the first on-treatment reevaluation. If partial stone dissolution is not seen by 12 months of Actigall therapy, the likelihood of success is greatly reduced.

Gallstone Prevention

The recommended dosage of Actigall for gallstone prevention in patients undergoing rapid weight loss is 600 mg/day (300 mg b.i.d.).

How Supplied

Actigall Capsules are opaque white and pink capsules imprinted “ACTIGALL” on one half and “300 mg” on the other half of the capsule in black.Bottles of 100 are supplied with child-resistant closures.(NDC0023-6145-01)Store at 20-25°C (68-77°F). [See USP controlled room temperature.] Dispense in a tight container (USP).Keep out of reach of children.Rx onlyDistributed by: Allergan USA, Inc.Irvine, CA 92612Revised: July 201773336US10

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