Ursodiol (Page 3 of 3)

14 CLINICAL STUDIES

14.1 Efficacy of Ursodeoxycholic Acid Administered at 13 to 15 mg/kg/day in 3 or 4 Divided Doses to PBC Patients

A U.S., multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of ursodeoxycholic acid at a dose of 13 to 15 mg/kg/day, administered in 3 or 4 divided doses in 180 patients with PBC (78% received four times a day dosage). Upon completion of the double-blind portion, all patients entered an open-label active treatment extension phase.

Treatment failure, the main efficacy endpoint measured during this study, was defined as death, need for liver transplantation, histologic progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal. After two years of double-blind treatment, the incidence of treatment failure was significantly (p<0.01) reduced in the ursodiol tablets, 250 mg group (20 of 86 (23%) as compared to the placebo group (40 of 86 (47). Time to treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, was also significantly (p<0.001) delayed in the ursodiol tablets, 250 mg treated group (n=86, 803.8±24.9 d vs. 641.1±24.4 d for the placebo group (n=86) on average) regardless of either histologic stage or baseline bilirubin levels (>1.8 or <1.8 mg/dL).

Using a definition of treatment failure, which excluded doubling of serum bilirubin and voluntary withdrawal, time to treatment failure was significantly delayed in the ursodiol tablets, 250 mg group. In comparison with placebo, treatment with ursodiol tablets, 250 mg resulted in a significant improvement in the following serum hepatic biochemistries when compared to baseline: total bilirubin, SGOT, alkaline phosphatase and IgM.

14.2 Efficacy of Ursodiol Administered at 14 mg/kg/day as a Once Daily Dose to PBC Patients

A second study conducted in Canada randomized 222 PBC patients to ursodiol, 14 mg/kg/day or placebo, administered as a once daily dose in a double-blind manner during a two-year period. At two years, a statistically significant (p<0.001) difference between the two treatments (n=106 for the ursodiol tablets, 250 mg group and n=106 for the placebo group), in favor of ursodiol, was demonstrated in the following: reduction in the proportion of patients exhibiting a more than 50% increase in serum bilirubin; median percent decrease in bilirubin (-17.12% for the ursodiol tablets, 250 mg group vs. +20.00% for the placebo group), transaminases (-40.54% for the ursodiol tablets, 250 mg group vs. +5.71% for the placebo group) and alkaline phosphatase (-47.61% for the ursodiol tablets, 250 mg group vs. -5.69% for the placebo group); incidence of treatment failure; and time to treatment failure. The definition of treatment failure included: discontinuing the study for any reason; a total serum bilirubin level greater than or equal to 1.5 mg/dl or increasing to a level equal to or greater than two times the baseline level; and the development of ascites or encephalopathy. Evaluation of patients at 4 years or longer was inadequate due to the high drop-out rate (n=10 withdrew from the ursodiol tablets, 250 mg group vs. n=15 from the placebo group) and small number of patients. Therefore, death, need for liver transplantation, histological progression by two stages or to cirrhosis, development of varices, ascites or encephalopathy, marked worsening of fatigue or pruritus, inability to tolerate the drug, doubling of serum bilirubin and voluntary withdrawal were not assessed.

14.3 Efficacy of Ursodiol Administered in Twice a Day Versus Four Times a Day Divided Dosing Schedules to PBC Patients

A randomized, two-period crossover study in fifty PBC patients compared efficacy of ursodiol tablets, 250 mg in twice a day versus four times a day divided dosing schedules in 50 patients for 6 months in each crossover period. Mean percent changes from baseline in liver test results and Mayo risk score (n=46) and serum enrichment with UDCA (n=34) were not statistically significant with any dosage at any time interval. This study demonstrated that UDCA (13 to 15 mg/kg/day) given twice a day is equally effective to UDCA given four times a day. In addition, ursodiol tablets, 250 mg was given as a single versus three times a day dosing schedules in 10 patients. Due to the small number of patients in this arm of the study, it was not possible to conduct statistical comparisons between these regimens.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ursodiol Tablets USP, 250 mg are White to off-white, oval, biconvex, film coated tablets debossed with “1127” on one side and plain on other side and are supplied as follows:

NDC 70771-1407-1 in bottles of 100 tablets

NDC 70771-1407-5 in bottles of 500 tablets

Ursodiol Tablets USP, 500 mg are White to off-white, oval, biconvex, film coated tablets debossed with “1128” on one side and breakline on other side. and are supplied as follows:

NDC 70771-1408-1 in bottles of 100 tablets

NDC 70771-1408-5 in bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container.

Half-tablets (scored ursodiol 500 mg tablets broken in half) maintain acceptable quality for up to 28 days when stored in the current packaging (bottles) at 20ºC to 25ºC (68ºF to 77ºF). Due to the bitter taste, the halved segments should be stored separately from the whole tablets [see Dosage and Administration (2.2)].

17 PATIENT COUNSELING INFORMATION

17.1 Appropriate Treatments

Patients with the following conditions should be instructed to receive appropriate management measures: variceal bleeding, hepatic encephalopathy, ascites, in need of an urgent liver transplant or hepatic function deterioration [see Warnings and Precautions (5)].

Caution has to be exercised to maintain the bile flow of the patients taking ursodiol.

17.2 Drug Interactions

Patients should be informed that absorption of ursodiol may be reduced if they are taking bile acid sequestering agents, such as cholestyramine and colestipol, aluminum-based antacids, or drugs known to alter the metabolism of cholesterol [see Drug Interactions (7)].

Manufactured by:

Cadila Healthcare Ltd.

Baddi, India

Rev.: 05/21

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 70771-1407-1 in bottles of 100 tablets

Ursodiol Tablets USP, 250 mg

100 Tablets

Rx only

250 mg
(click image for full-size original)

NDC 70771-1408-1 in bottles of 100 tablets

Ursodiol Tablets USP, 500 mg

100 Tablets

Rx only

500 mg
(click image for full-size original)
URSODIOL ursodiol tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70771-1407
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
URSODIOL (URSODIOL) URSODIOL 250 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE 2910 (6 MPA.S)
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
POLYETHYLENE GLYCOL 400
POLYETHYLENE GLYCOL 8000
POVIDONE K30
SILICON DIOXIDE
SODIUM LAURYL SULFATE
SODIUM STARCH GLYCOLATE TYPE A POTATO
TITANIUM DIOXIDE
Product Characteristics
Color WHITE (White to off-white) Score no score
Shape OVAL Size 15mm
Flavor Imprint Code 1127
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:70771-1407-1 100 TABLET in 1 BOTTLE None
2 NDC:70771-1407-5 500 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA211145 11/07/2018
URSODIOL ursodiol tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70771-1408
Route of Administration ORAL DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
URSODIOL (URSODIOL) URSODIOL 500 mg
Inactive Ingredients
Ingredient Name Strength
HYPROMELLOSE 2910 (6 MPA.S)
MAGNESIUM STEARATE
MICROCRYSTALLINE CELLULOSE
POLYETHYLENE GLYCOL 400
POLYETHYLENE GLYCOL 8000
POVIDONE K30
SILICON DIOXIDE
SODIUM LAURYL SULFATE
SODIUM STARCH GLYCOLATE TYPE A POTATO
TITANIUM DIOXIDE
Product Characteristics
Color WHITE (White to off-white) Score 2 pieces
Shape OVAL Size 18mm
Flavor Imprint Code 1128
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:70771-1408-1 100 TABLET in 1 BOTTLE None
2 NDC:70771-1408-5 500 TABLET in 1 BOTTLE None
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA211145 11/07/2018
Labeler — Cadila Healthcare Limited (918596198)
Registrant — Cadila Healthcare Limited (677605858)
Establishment
Name Address ID/FEI Operations
Cadila Healthcare Limited 677605858 ANALYSIS (70771-1407), ANALYSIS (70771-1408), MANUFACTURE (70771-1407), MANUFACTURE (70771-1408)

Revised: 05/2021 Cadila Healthcare Limited

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