Actigall

Actigall information, interactions and side effects, 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:

actigall

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.

INDICATIONS

  1. 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.
  2. Actigall is indicated for the prevention of gallstone formation in obese patients experiencing rapid weight loss.

DOSAGE AND ADMINISTRATION

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 1-3 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. (NDC 52544-930-01)

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

Dispense in tight container (USP).

Keep out of reach of children.

Manufactured By: Watson Pharma Private Limited, Verna, Salcette Goa 403 722 INDIA. Distributed By: Watson Pharma, Inc., Corona, CA 92880 USA. Revised: March 2009

This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

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

 

Urs odiol 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)

 

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.

This monograph has been modified to include the generic and brand name in many instances.

PRECAUTIONS

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.

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 intra rectal 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.

This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

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 6-37 months without symptoms by 7 patients. The LD for ursodiol in rats is over 5000 mg/kg given over 7-10 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.

CONTRAINDICATIONS

  1. 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.
  2. 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.
  3. Allergy to bile acids.

This monograph has been modified to include the generic and brand name in many instances.

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