Urso: Indications, Dosage, Precautions, Adverse Effects
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Urso - Product Information

Manufacture: Actavis
Country: Canada
Condition: Biliary Cirrhosis, Gallbladder Disease
Class: Gallstone solubilizing agents
Form: Tablets
Ingredients: ursodiol, carnauba wax, dibutyl sebacate, ethylcellulose aqueous (cetyl alcohol, ethylcellulose, hydrogen peroxide, sodium lauryl sulfate), hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and sodium starch glycolate

Summary product information

Route of AdministrationDosage Form /StrengthClinically Relevant Non-medicinal Ingredients
oraltablet 250 mg, 500 mgNone
For a complete listing see DOSAGE FORMS,COMPOSITION AND PACKAGING section.

Indications and clinical use

URSO and URSO DS (ursodiol), also known as ursodeoxycholic acid (UDCA) are 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 URSO and URSO DS in the management of cholestatic liver diseases should be based on the biochemical parameters of cholestasis, as described above, 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. (see WARNINGS and PRECAUTIONS and DOSAGE and ADMINISTRATION).

URSO and URSO DS are not indicated for the treatment of decompensated cirrhosis.

Geriatrics:

Appropriate studies with URSO and URSO DS have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of URSO and URSO DS in the elderly are not expected.

Pediatrics:

The safety and effectiveness of URSO and URSO DS in children have not been established.

Contraindications

Patients with complete biliary obstruction of extrahepatic origin; patients with widespread intrahepatic obstruction and patients who are hypersensitive to ursodiol or to any ingredient in the formulation For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

Warnings and precautions

Carcinogenesis and Mutagenesis

URSO and URSO DS 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 (see TOXICOLOGY).

Hepatic/Biliary/Pancreatic

Patients with variceal 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.

Special Populations

Pregnant Women

There are no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, URSO and URSO DS 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 foetus. (See also TOXICOLOGY.)

Nursing Women

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

Pediatrics

The safety and effectiveness of URSO and URSO DS in children have not been established.

Geriatrics

Appropriate studies with URSO and URSO DS have not been performed in the geriatric population. However, geriatric-specific problems that would limit the use or usefulness of URSO and URSO DS in the elderly are not expected.

Monitoring and Laboratory Tests

Lithocholic acid, one of the metabolites of ursodeoxycholic acid (URSO and URSO DS) is hepatotoxic unless it is effectively detoxified in the liver. Therefore, the following tests are important for patient monitoring:

Serum liver function tests ( γ-GT, alkaline phosphatase, AST, ALT) and bilirubin levels 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 significant (see DOSAGE and ADMINISTRATION and WARNINGS and PRECAUTIONS).

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

Adverse reactions

Adverse Drug Reaction Overview

Adverse events observed in clinical trials are tabulated and described below. In a 180 patient placebo-controlled trial in primary biliary cirrhosis, the common adverse events (i.e. ≥ 1 %) included leukopenia, skin rash, diarrhea, blood creatinine increased, blood glucose increased, and peptic ulcer. In a second trial with 60 patients, the frequency of treatment-emergent adverse event reporting was higher with the most common (defined as ≥ 5%) being asthenia, dyspepsia, edema peripheral, hypertension, nausea, GI disorder, chest pain, and pruritus. In this second trial there were 4 serious adverse events: 1 patient with diabetes mellitus, 1 patient with breast nodule and 2 patients with fibrocystic breast disease. None of these events were considered related to the medication. At the recommended dosage, ursodiol is well-tolerated and has no significant adverse events.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The adverse reactions in Table 1 below were observed in clinical trials in primary biliary cirrhosis with 180 patients (89 randomized to URSO treatment, 91 to placebo treatment). Adverse events are reported regardless of attribution to the test medication. Adverse reactions occurring at a rate of 1% or higher in the URSO group, and that are higher than placebo are included in Table 1.

Diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other side effects are not included, because they occurred at the same rate or a lower rate than placebo.

Table 1: Adverse events with a frequency ≥ 1% Observed in a Clinical Trial of 180 patients
Adverse event (ordered by MedDRA System Organ Class)Visit at 12 MonthsVisit at 24 Months
UDCA1
n (%)
Placebo
n (%)
UDCA1 n (%)Placebo
n (%)
Blood and lymphatic system disordersLeukopenia--2(2.63)-
Gastrointestinal disordersDiarrhea--1 (1.32)-
Peptic ulcer--1 (1.32)-
InvestigationsBlood creatinine increased--1 (1.32)-
Blood glucose increased1 (1.18)-1 (1.32)-
Skin and subcutaneous tissue disordersRash--2 (2.63)-

1 UDCA=Ursodeoxycholic acid=Ursodiol =URSO
Note: Those AEs occurring at the same or higher incidence in the placebo as in the UDCA group have been deleted from this table (this includes diarrhea and thrombocytopenia at 12 months, nausea/vomiting, fever and other toxicity).

In a randomized, cross over study in sixty PBC patients, four patients experienced one serious adverse event each (diabetes mellitus, breast nodule, and fibrocystic breast disease (2 patients)). No deaths occurred in the study. Forty-three patients (43/71.7%) experienced at least one treatment-emergent adverse event (TEAEs) during the study. The most common (defined as ≥5%) TEAEs were asthenia, (11.7%), dyspepsia (10%), edema peripheral (8.3%), hypertension (8.3%), nausea (8.3%), GI disorders (5%), chest pain (5%), and pruritus (5%). These nine TEAEs included abdominal pain and asthenia (1 patient), nausea (3 patients), dyspepsia (2 patients), and anorexia and esophagitis (1 patient each). One patient on the BID regimen (total dose 1000 mg) withdrew due to nausea. All of these nine TEAEs except esophagitis were observed with the BID regimen at a total daily dose of 1000 mg or greater.

Table 2: Treatment-Emergent Adverse Events (TEAEs) with a Frequency of ≥ 1 % Observed in a Clinical Trial of 60 PBC patients
Adverse event
(ordered by MedDRA System Organ Class)
TEAEs, n (%)
Blood and lymphatic system
disorders
Anemia1 (1.7)
Lymphadenopathy2 (3.3)
Cardiac disordersArrhythmia2 (3.3)
Cardiovascular disorder2 (3.3)
Ear and labyrinth disordersDeafness1 (1.7)
Vertigo1 (1.7)
Eye disordersCataract2 (3.3)
Eye disorder1 (1.7)
Retinal disorder1 (1.7)
Gastrointestinal disordersAbdominal pain2 (3.3)
Diarrhea2 (3.3)
Dyspepsia6 (10)
Dysphagia1 (1.7)
Esophagitis1 (1.7)
Flatulence1 (1.7)
Gastrointestinal disorder3 (5.0)
Nausea5 (8.3)
Salivary gland enlargement1 (1.7)
Stomach ulcer1 (1.7)
General disorders and
administration site conditions
Asthenia7 (11.7)
Chest pain3 (5.0)
Chest pain substernal1 (1.7)
Cyst1 (1.7)
Edema5 (8.3)
Edema generalized1 (1.7)
Edema peripheral5 (8.3)
Granuloma1 (1.7)
Hemorrhagic ulcer1 (1.7)
Pain1 (1.7)
Hepatobiliary disordersBiliary pain1 (1.7)
Immune system disordersAmyloidosis1 (1.7)
Infections and infestationsBronchitis1 (1.7)
Cystitis1 (1.7)
Herpes simplex1 (1.7)
Infection1 (1.7)
Otitis media1 (1.7)
Pharyngitis1 (1.7)
Pneumonia1 (1.7)
Rhinitis2 (3.3)
Urinary tract infection1 (1.7)
Vaginitis1 (1.7)
Metabolism and nutrition
disorders
Anorexia1 (1.7)
Diabetes mellitus2 (3.3)
Musculoskeletal and connective
tissue disorders
Back pain1 (1.7)
Bone disorder1 (1.7)
Bone fracture spontaneous1 (1.7)
Neoplasms benign, malignant and
unspecified (incl cysts and
polyps)
Breast neoplasm1 (1.7)
Lung nodule1 (1.7)
Plantar warts1 (1.7)
Nervous system disordersDizziness2 (3.3)
Headache1 (1.7)
Migraine1 (1.7)
Paresthesia1 (1.7)
Reproductive system and breast
disorders
Breast nodule1 (1.7)
Fibrocystic breast disease2 (3.3)
Menorrhagia1 (1.7)
Respiratory, thoracic and
mediastinal disorders
Dyspnea1 (1.7)
Lung disorder1 (1.7)
Respiratory disorder1 (1.7)
Sore nose2 (3.3)
Skin and subcutaneous tissue
disorders
Acne2 (3.3)
Miliaria1 (1,7)
Pruritus3 (5.0)
Psoriasis1 (1.7)
Rash1 (1.7)
Skin disorder2 (3.3)
Skin hypertrophy1 (1.7)
Vascular disordersHypertension5 (8.3)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Analysis of the data in the trial with 180 patients (Table 1) revealed no reports of adverse events at rates <1 % with the exception of those adverse events that occurred at the same or at a higher incidence in the treatment group than placebo. No data for TEAEs occurring at rates <1 % in the trial of 60 patients (Table 2) are available due to the small sample size.

Abnormal Hematologic and Clinical Chemistry Findings

In the placebo-controlled trial with 180 patients, change from baseline in hematologic parameters and non-hepatic clinical chemistry were analyzed. Statistically significant differences from baseline are reported in Tables 3 and 4.

Table 3: Hematologic Parameters: Changes from Baseline
BaselineEndpointChange from Baseline
UDCAPlaceboUDCAPlaceboUDCA
(±SD)
Placebo
(±SD)
WBCMean
(±SD)
5.9
(2.0)
6.2
(4.1)
5.5
(1.6)
5.8
(2.4)
-0.5**
(1.4)
-0.5
(4.3)
n88878375
PlateletsMean
(±SD)
238.5
(92.5)
245.4
(112.4)
211.2
(87.2)
223.9
(94.3)
-29.4**
(39.3)
-17.7*
(58.0)
n86868274

* Statistically different from zero, p < 0.05
**Statistically different from zero, p < 0.01

There was a significant decrease (p<0.01) in WBC and platelets in the UDCA-treated group from baseline and a significant (p<0.05) decrease in platelets in the placebo group. There was no significant change in haemoglobin.

Table 4: Clinical Chemistries: Changes from Baseline
BaselineEndpointChange from Baseline
UDCAPlaceboUDCAPlaceboUDCA
(±SD)
Placebo
(±SD)
Calcium
(mg/dL)
Mean
(±SD)
9.49a
(0.40)
9.47
(0.40)
9.39
(0.43)
9.30
(0.51)
-0.12**,a
(0.37)
-0.19**
(0.37)
n89918376
Cholesterol
(mg/dL)
Mean
(±SD)
287.73a
(121.12)
276.03
(105.22)
223.53
(56.80)
261.46
(83.53)
-67.39**,b
(93.31)
-11.32*
(47.70)
n89918376
Creatinine
(mg/dL)
Mean
(±SD)
0.86
(0.19)
0.84
(0.21)
0.92
(0.19)
0.92
(0.26)
0.07**a
(0.18)
0.07**
(0.23)
n89918376
Total
Thyroxine
(μg/dL)
Mean
(±SD)
8.66a
(1.63)
8.60
(2.27)
7.96
(1.87)
8.27
(3.25)
-0.69*,a
(1.52)
-0.49
(2.52)
n87908374
Triglycerides
(mg/dL)
Mean
(±SD)
102.82a
(49.25)
117.11
(70.57)
114.18
(55.13)
121.52
(57.56)
11.76*,a
(44.38)
3.00
(56.74)
n88898375

** Statistically different from zero, p < 0.01
* Statistically different from zero, p < 0.05
ap = ns, UDCA versus placebo
bp = 0.0001, UDCA versus placebo

All the non-hepatic clinical chemistries at baseline were not significantly different (p>0.05) between the UDCA- and placebo- treated groups. In the UDCA group there was a significant (p>0.05) decrease from baseline in calcium, cholesterol and total thyroxine and a significant increase (p>0.05) in creatinine and triglycerides. In the placebo group there was a significant (p>0.05) decrease in cholesterol and significant increase (p>0.05) in calcium and creatinine. There was no significant change seen for sodium, potassium, phosphorus, HDL, and AMA.

Post-Market Adverse Drug Reactions

The following adverse reactions, presented by system organ class in alphabetical order, have been identified during post-approval use of ursodiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • Blood and lymphatic system disorders: anemia, eosinophilia, leukopenia, neutropenia, thrombocytopenia.
  • Cardiac disorders: palpitations.
  • Gastrointestinal disorders: abdominal discomfort, abdominal pain, cheilitis, constipation, diarrhea, dyspepsia, nausea, vomiting.
  • General disorders and administration site conditions: malaise, peripheral edema, pyrexia.
  • Hepatobiliary disorders: jaundice (or aggravation of pre-existing jaundice)
  • Immune system disorders: angioedema and laryngeal edema, drug hypersensitivity to include facial edema, urticaria.
  • Investigations: blood glucose increased, blood urine present, weight decreased, weight increased, ALT increased, AST increased, blood alkaline phosphatase increased, blood bilirubin increased, γ-GT increased, transaminases increased. Rare instances of severe liver injury (elevated values for ALT/AST, ALP, γ-GTP and total bilirubin) have been reported with URSO.
  • Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: dizziness, headache.
  • Respiratory, thoracic and mediastinal disorders: cough, interstitial lung disease.
  • Skin and subcutaneous tissue disorder: alopecia, dermatitis exfoliative, erythema, lichenoid keratosis, photosensitivity reaction, pruritus, rash.

Drug interactions

Overview

Bile acid sequestering agents may interfere with the action of URSO and URSO DS by reducing absorption. Aluminum based antacids adsorb bile acids in vitro and may act in the same manner as sequestering agents, thereby interfering with the action of URSO and URSO DS. Ursodiol has been shown to be an inducer of CYP3A however the clinical relevance is not known. Metabolic interactions with compounds metabolized by cytochrome P4503A are to be expected.

Drug-Drug Interactions

Table 5: Drug-Drug Interactions
EffectClinical comment
Bile acid sequestrants (i.e. cholestyramine or cholestipol)Reduces ursodiol absorptionMay interfere with the action of URSO and URSO DS
Aluminum based antacidsReduces ursodiol absorption Adsorbs bile acid in vitroMay be expected to interfere with URSO and URSO DS
Cytochrome P4503A substrates cyclosporine, nitrendipine and dapsoneMetabolic interaction.Metabolic interactions with compounds substrates cyclosporine, metabolized by cytochrome P4503A are to be expected.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and administration

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 significant (see INDICATIONS and CLINICAL USE and WARNINGS AND PRECAUTIONS).

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

Recommended Dose

The recommended adult dosage for URSO and URSO DS (ursodiol) in the treatment of PBC is 13-15 mg/kg/day administered in two to four divided doses with food. The URSO DS scored tablet can be broken in halves to provide recommended dosage.

Missed Dose

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for your next dose, skip the dose you missed and take your next regularly scheduled dose. Do not take a double dose.

Overdosage

Accidental or intentional overdosage with ursodiol has not been reported. The most severe manifestation of overdosage would likely consist of diarrhea that should be treated symptomatically.

Symptoms of acute toxicity in animal studies were salivation and vomiting in dogs, and ataxia, dyspnea, ptosis, agonal convulsions and coma in hamsters.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and clinical pharmacology

Mechanism of Action

Ursodiol, 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 ursodiol 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 URSO and URSO DS 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 URSO and URSO DS might be the common denominator of these two mechanisms.

Pharmacodynamics

During chronic administration, ursodiol becomes a major biliary and plasma bile acid. At a chronic dose of 13-15 mg/kg/day, ursodiol constitutes 30-50% of biliary and plasma bile acids.

Pharmacokinetics

Absorption

Ursodiol (UDCA) is normally present as a minor fraction of the total bile acids in humans (about 5%). Following oral administration, the majority of ursodiol is absorbed by passive diffusion and its absorption is incomplete.

Distribution

In healthy subjects, at least 70% of ursodiol (unconjugated) is bound to plasma protein. No information is available on the binding of conjugated ursodiol to plasma protein in healthy subjects or primary biliary cirrhosis (PBC) patients. However, since the efficacy of ursodiol 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, ursodiol 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, ursodiol is conjugated with glycine or taurine, then secreted into bile. These conjugates of ursodiol 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. Nonabsorbed ursodiol passes into the colon where it is mostly 7-dehydroxylated to lithocholic acid. Some ursodiol 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. Ursodiol is 7-dehydroxylated more slowly than chenodiol. For equimolar doses of ursodiol and chenodiol, steady state levels of lithocholic acid in biliary bile acids are lower during ursodiol administration than with chenodiol administration. Humans and chimpanzees can sulfate lithocholic acid. Although liver injury has not been associated with ursodiol 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 ursodiol.

Excretion

Ursodiol is excreted primarily in the feces. With treatment, urinary excretion increases, but remains less than 1%, except in severe cholestatic liver disease.

Storage and stability

URSO and URSO DS tablets should be stored at controlled room temperature at 15oC - 30oC in a closed container.

Half-tablets (scored URSO DS tablets broken in half) maintain acceptable quality for up to 28 days when stored in the current packaging (bottles) at 15oC-30 oC .

Special handling instructions

To prevent leakage of the active medicinal ingredient (ursodiol) from the cut tablets onto the surface of whole tablets and spreading the bitter taste, it is recommended that cut tablets be stored separately from whole tablets

Dosage forms, composition and packaging

250 mg tablet
URSO (ursodiol) is available in a strength of 250 mg as a white, elliptical, biconvex, film-coated tablet, engraved with “URS785" on one side. Available as bottles of 100 tablets.

500 mg tablet
URSO DS (ursodiol) is available in a strength of 500 mg as a white, elliptical, biconvex, scored, film-coated tablet, engraved with “URS790" on one side. Available as bottles of 100 tablets.

In addition to ursodiol as the active ingredient, URSO and URSO DS contain the following excipients: carnauba wax, dibutyl sebacate, ethylcellulose aqueous (cetyl alcohol, ethylcellulose, hydrogen peroxide, sodium lauryl sulfate), hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and sodium starch glycolate.