Cholemax

Capsule: White, hard gelatin capsule No.0 containing white powder.
Each capsule contains Ursodeoxycholic acid 250 mg.
Oral suspension: White, homogenous suspension, with strawberry yoghurt odour.
Ursodeoxycholic acid (UDCA) 250 mg/5 mL.
Excipients/Inactive Ingredients: Oral suspension: Liquid maltitol, glycerin, xanthan gum, carmellose sodium, citric acid, sodium citrate, sodium chloride, saccharin sodium, xylitol, ammonium glycyrrhizinate, methyl hydroxybenzoate, propyl hydroxybenzoate, strawberry flavor, yoghurt flavor, purified water.

Pharmacotherapeutic group: Bile Acid Preparation. ATC code: A05AA02 and A05B.
Pharmacology: Pharmacodynamics: Capsule: Ursodeoxycholic acid, the 7-β-hydroxyepimer of chenodeoxycholic acid (chenodiol), is a naturally occurring, hydrophilic bile acid found in small quantities in normal human bile (normally about 5% of total bile acids) and in the bile of certain animals.
The exact mechanism of action(s) of ursodeoxycholic acid in the dissolution of gallstones has not been fully elucidated, but it has been suggested that the drug suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol.
Despite aqueous insolubility of cholesterol, in the presence of dihydroxy bile acids cholesterol can be solubilized in aqueous media through the dispersion of cholesterol as liquid crystals or micelles.
Appear to have small inhibitory effect on synthesis and secretion of endogenous bile acids into bile, does not appear to affect secretion of phospholipids into bile.
Site of therapeutic action include the liver, bile and gut lumen.
In patients with gallstones, combined actions of ursodeoxycholic acid change the bile from cholesterol-precipitating to cholesterol-solubilizing, which results in dissolution of cholesterol stones.
Oral suspension: UDCA is a bile acid which effects a reduction in cholesterol in biliary fluid primarily by dispersing the cholesterol and forming a liquid-crystal phase. UDCA affects the enterohepatic circulation of bile salts by reducing the ileal reabsorption of endogenous more hydrophobic and potentially toxic salts such as cholic and chenodeoxycholic acids.
In-vitro studies show that UDCA has a direct hepatoprotective effect and reduces the hepatotoxicity of hydrophobic bile salts. Immunological effects have also been demonstrated with a reduction in abnormal expression of HLS Class I antigens on hepatocytes as well as suppression of cytokine and interleukin production.
Cystic fibrosis - Paediatric population: From clinical reports long-term experience up to 10 years and more is available with UDCA treatment in paediatric patients suffering from cystic fibrosis associated hepatobiliary disorders (CFAHD). There is evidence that treatment with UDCA can decrease bile duct proliferation, halt progression of histological damage and even reverse hepatobiliary changes if given at early stage of CFAHD. Treatment with UDCA should be started as soon as the diagnosis of CFAHD is made in order to optimise treatment effectiveness.
Pharmacokinetics: Capsule: About 90% of a therapeutic dose of ursodeoxycholic acid is absorbed in the small bowel after oral administration. After absorption, ursodeoxycholic acid enters the portal vein and undergoes efficient extraction from portal blood by the liver (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. Ursodeoxycholic acid 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 ursodeoxycholic acid 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. With repeated dosing, bile ursodeoxycholic acid concentrations reach steady state in about 3 weeks.
Beyond conjugation, ursodeoxycholic acid is not altered or catabolized appreciably by the liver or intestinal mucosa. Ursodeoxycholic acid can be both oxidized and reduced at the 7- carbon, yielding either 7-keto-lithocholic acid or lithocholic acid, respectively. Free ursodeoxycholic acid, 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 ursodeoxycholic acid is reconjugated by the liver. Eighty percent (80%) 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 insoluble lithocholyl conjugates that are excreted into bile and lost in feces.
Oral suspension: UDCA occurs naturally in the body. When given orally it is rapidly and completely absorbed. It is 96-98% bound to plasma proteins and efficiently extracted by the liver and excreted in the bile as glycine and taurine conjugates. In the intestine some of the conjugates are deconjugated and reabsorbed. The conjugates may also be dehydroxylated to lithocholic acid, part of which is absorbed, sulphated by the liver and excreted via the biliary tract.
Toxicology: Preclinical safety data: Oral suspension: Acute toxicity: Acute toxicity studies in animals have not revealed any toxic damage.
Chronic toxicity: Subchronic toxicity studies in monkeys showed hepatotoxic effects in the groups given high doses, including functional changes (e.g. liver enzyme changes) and morphological changes such as bile duct proliferation, portal inflammatory foci and hepatocellular necrosis. These toxic effects are most likely attributable to lithocholic acid, a metabolite of UDCA, which in monkeys unlike humans is not detoxified. Clinical experience confirms that the described hepatotoxic effects are of no apparent relevance in humans.
Carcinogenic and mutagenic potential: Long-term studies in mice and rats revealed no evidence of UDCA having carcinogenic potential.
In vitro and in vivo genetic toxicology tests with UDCA were negative.
The tests with UDCA revealed no relevant evidence of a mutagenic effect.
Toxicity to reproduction: In studies in rats, tail malformations occurred after a dose of 2000 mg of UDCA per kg of body weight. In rabbits, no teratogenic effects were found, although there were embryotoxic effects (from a dose of 100 mg per kg of body weight). UDCA had no effect on fertility in rats and did not affect peri-/post-natal development of the offspring.

Capsule: Cholemax capsules are used for the treatment of dissolution of radiolucent cholesterol gallstones, less than 20 mm in diameter.
The prevention of gallstone formation in obese patients undergoing rapid weight loss.
Oral suspension: Treatment of primary biliary cholangitis (PBC); For the dissolution of radiolucent gallstones in patients with a functioning gall bladder; Hepatobiliary disorders associated with cystic fibrosis in children aged 1 month to 18 years.

Capsule: Recommended Dose: Gallstone dissolution: 8-10 mg/kg/day in 2 or 3 divided doses.
Prevention of Gallstones: 300 mg twice daily.
Mode of Administration: Orally.
Oral suspension: There are no age restrictions on the use of ursodeoxycholic acid (UDCA) suspension in the treatment of PBC and for the dissolution of radiolucent gallstones. The following daily dose is recommended for the various indications: For the treatment of primary biliary cholangitis (PBC): The daily dose depends on body weight, and is approximately 14±2 mg UDCA per kg of body weight.
For the first 3 months of treatment, UDCA suspension should be taken divided over the day.
When the liver function parameters improve, the daily dose can be administered once a day in the evening. (See Table 1.)

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UDCA suspension should be taken in accordance with the dosage regimen given in the previous text. The oral suspension must be taken regularly.
The use of UDCA suspension in PBC may be continued indefinitely.
For dissolution of cholesterol gallstones: Approximately 10 mg of UDCA per kg of body weight daily, equivalent to: See Table 2.

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UDCA suspension should be taken in the evening at bedtime. The oral suspension must be taken regularly.
The time required for dissolution of gallstones is likely to range from 6 to 24 months depending on stone size and composition.
Follow-up cholecystograms or ultrasound investigation may be useful at 6 months intervals until the gallstones have disappeared.
Treatment should be continued until 2 successive cholecystograms and/or ultrasound investigations 4-12 weeks apart have failed to demonstrate gallstones. This is because these techniques do not permit reliable visualisation of stone less than 2 mm in diameter. The likelihood of recurrence of gallstones after dissolution by bile acid treatment has been estimated as up to 50% at 5 years. The efficiency of UDCA in treating radio-opaque or partially radiopaque gallstones has not been tested but these are generally thought to be less soluble than radiolucent stones. Non-cholesterol stones account for 10-15% of radiolucent stones and may not be dissolved by bile acids.
Older people: There is no evidence to suggest that any alteration in the adult dose is needed but the relevant precautions should be taken into account.
Paediatric population: Cholesterol rich gallstones and PBC are very rare in children but when they occur, dosage should be related to body weight. There are no adequate data on the efficacy and safety in this population.
Hepatobiliary disorders associated with cystic fibrosis: Children with cystic fibrosis aged 1 month to 18 years: 20 mg/kg/day in 2-3 divided doses, with a further increase to 30 mg/kg/day if necessary.
Very rarely, children under 10 kg body weight are affected. In this case, a commercially available single-use syringe should be used.
(Note: a syringe is not provided in the pack).
Up to 10 kg body weight: Dosing 20 mg UDCA/kg/day.
Measuring device: single-use 2 ml graduated syringe (not provided). (See Table 3.)

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More than 10 kg body weight (BW): Dosing 20-25 mg UDCA/kg/day.
Measuring device: measuring cup. (See Tables 4 and 5.)

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Capsule: Symptoms: Neither accidental nor intentional overdosage with ursodeoxycholic acid has been reported. The most likely manifestation of severe overdose with ursodeoxycholic acid would likely be diarrhea.
Treatment: Should be treated symptomatically.
Oral suspension: Diarrhoea may occur in cases of overdose. In general, other symptoms of overdose are unlikely, because the absorption of UDCA decreases with increasing dose and therefore more is excreted with the faeces.
No specific countermeasures are necessary and the consequences of diarrhoea should be treated symptomatically with restoration of fluid and electrolyte balance.
Additional information on special populations: Long-term, high-dose UDCA therapy (28-30 mg/kg/day) in patients with primary sclerosing cholangitis (off-label use) was, associated with higher rates of serious adverse events.

Capsule: Hypersensitivity or intolerance to ursodeoxycholic acid, bile acid or any of the components of the formulations.
Do not use ursodeoxycholic acid for dissolution of calcified cholesterol stones, radiopaque stones, or radiolucent bile pigment stones.
Do not use in patients with compelling reasons for cholecystectomy including unremitting acute cholecystitis, cholangitis, biliary obstruction, gallstone pancreatitis, or biliary-GI fistula.
Oral suspension: UDCA suspension should not be used in patients with: Acute inflammation of the gall bladder or biliary tract.
Occlusion of the biliary tract (occlusion of the common bile duct or cystic duct)
Frequent episodes of biliary colic.
Radio-opaque calcified gallstones.
Impaired contractility of the gall bladder.
Hypersensitivity to bile acids or any excipient of the formulation.
When used in hepatobiliary disorders associated with cystic fibrosis in children aged 1 month to 18 years: Unsuccessful portoenterostomy or without recovery of good bile flow in children with biliary atresia.

Capsule: Ursodeoxycholic acid has not been associated with the liver damage; however, measure AST and ALT at initiation of and during therapy as indicated by particular clinical circumstances.
Monitoring: perform ultrasound images of gall bladder at 6-month intervals for first year of therapy to monitor gallstone response. If partial stone dissolution is not seen by 12 months of therapy, likelihood of success is greatly reduced.
Oral suspension: UDCA suspension should be taken under medical supervision.
During the first 3 months of treatment, liver function parameters AST (SGOT), ALT (SGPT) and γ-GT should be monitored by the physician every 4 weeks, thereafter every 3 months. Apart from allowing for identification of responders and non-responders in patients being treated for PBC, this monitoring would also enable early detection of potential hepatic deterioration, particularly in patients with advance stage PBC.
When used for treatment of advanced stage of primary biliary cholangitis: In very rare cases decompensation of hepatic cirrhosis has been observed, which partially regressed after the treatment was discontinued.
In patients with PBC, in rare cases the clinical symptoms may worsen at the beginning of treatment, e.g. the itching may increase. In this case the dose of UDCA suspension should be reduced to 250 mg daily and then gradually increased to the recommended dose described in Dosage & Administration.
If diarrhoea occurs, the dose must be reduced and in cases of persistent diarrhoea, the therapy should be discontinued.
When used for dissolution of cholesterol gallstones: In order to assess therapeutic progress and for timely detection of any calcification of the gallstones, depending on stone size, the gall bladder should be visualised (oral cholecystography) with overview and occlusion views in standing and supine positions (ultrasound control) 6-10 months after the beginning of treatment.
If the gall bladder cannot be visualised on X-ray images, or in cases of calcified gallstones, impaired contractility of the gall bladder or frequent episodes of biliary colic, UDCA suspension should not be used.
Female patients taking UDCA for dissolution of gallstones should use an effective non-hormonal method of contraceptive, since hormonal contraceptives may increase biliary lithiasis (see Interactions and Use in Pregnancy & Lactation).
This medicinal product contains 13 mg sodium per 5 ml of suspension, equivalent to 0.65% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Effects on ability to drive and use machine: UDCA has no or negligible influence on the ability to drive and use machines.

Oral suspension: Animal studies did not show an influence of UDCA on fertility (see Pharmacology: Toxicology: Preclinical safety data under Actions). Human data on fertility effects following treatment with UDCA are not available.
Pregnancy: Capsule: Category B.
For safety reasons, treatment should not be carried out during the first trimester of pregnancy. As with any drug, if the patient is pregnant seeks the advice of a health care professional before using this product.
Oral suspension: There are no or limited amounts of data on the use of UDCA in pregnant women. Studies in animals have shown reproductive toxicity during the early phase of gestation (see Pharmacology: Toxicology: Preclinical safety data under Actions). UDCA suspension must not be used during pregnancy unless clearly necessary.
Women of childbearing potential should be treated only if they use reliable contraception: non-hormonal or low-oestrogen oral contraceptive measures are recommended. However, in patients taking UDCA for dissolution of gallstones, effective non-hormonal contraception should be used, since hormonal oral contraceptives may increase biliary lithiasis.
The possibility of a pregnancy must be excluded before beginning treatment.
Lactation/Breast-feeding: Capsule: Since there are insufficient data on the passage of ursodeoxycholic acid into breast-milk, it must not be used during breast-feeding.
Oral suspension: According to few documented cases of breastfeeding women milk levels of UDCA are very low and probably no adverse reactions are to be expected in breastfed infants.

Capsule: Gallstone dissolution: Abdominal pain, viral infection, headache, dyspepsia, upper respiratory tract infection, nausea, sinusitis, constipation, vomiting, pharyngitis, arthralgia, flatulence, back pain, cough, bronchitis, urinary tract infection, arthritis, myalgia, allergy, cholecystitis, rhinitis, fatigue.
Prevention of gallstone formation: Constipation, diarrhea, headache, nausea, dizziness, vomiting, upper respiratory tract infection, back pain, viral infection, fatigue, influenza-like symptoms, abdominal pain, musculoskeletal pain, dysmenorrhea, alopecia, sinusitis, flatulence.
Oral suspension: The evaluation of undesirable effects is based on the following frequency data: See Table 6.

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Gastrointestinal disorders: In clinical trials, reports of pasty stools or diarrhoea during UDCA therapy were common. Very rarely, severe right upper abdominal pain has occurred during the treatment of PBC.
Hepatobiliary disorders: During treatment with UDCA, calcification of gallstones can occur in very rare cases.
During therapy of the advanced stages of PBC, in very rare cases decompensation of hepatic cirrhosis has been observed, which partially regressed after the treatment was discontinued.
Skin and subcutaneous tissue disorders: Very rarely, urticaria can occur.

Capsule: Antacids (Aluminum-containing): Decreased absorption of ursodeoxycholic acid.
Bile acid sequestrants: Decreased absorption of ursodeoxycholic acid. Administer bile acid sequestrants (cholestyramine, colestipol) at least 2 hours before or after ursodeoxycholic acid.
Clofibrate: Possible reduced efficacy of ursodeoxycholic acid because of increased hepatic cholesterol secretion caused by clofibrate (and possibly other antilipemic drugs).
Estrogen: Possible reduced efficacy of ursodeoxycholic acid because of increased hepatic cholesterol secretion caused by estrogen.
Hormonal contraceptives: Possible reduced efficacy of ursodeoxycholic acid because of increased hepatic cholesterol secretion caused by oral contraceptives.
Oral suspension: UDCA suspension should not be administered concomitantly with colestyramine, colestipol or antacids containing aluminium hydroxide and/or smectite (aluminium oxide), because these preparations bind UDCA in the intestine and thereby inhibit its absorption and efficacy. Should the use of a preparation containing one of these substances be necessary, it must be taken at least 2 hours before or after UDCA suspension.
UDCA suspension can affect the absorption of ciclosporin from the intestine. In patients receiving ciclosporin treatment, blood concentrations of this substance should therefore be checked by the physician and the ciclosporin dose adjusted if necessary.
In isolated cases, UDCA suspension can reduce the absorption of ciprofloxacin.
In a clinical study in healthy volunteers concomitant use of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in slightly elevated plasma levels of rosuvastatin. The clinical relevance of this interaction also with regard to other statins is unknown.
UDCA has been shown to reduce the peak plasma concentrations (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring of the outcome of concurrent use of nitrendipine and UDCA is recommended. An increase in the dose of nitrendipine may be necessary. An interaction with a reduction of the therapeutic effect of dapsone was also reported. These observations, together with in-vitro findings, could indicate a potential for UDCA to induce cytochrome P450 3A enzymes. Induction has, however, not been observed in a well-designed interaction study with budesonide, which is a known cytochrome P450 3A substrate.
Oestrogenic hormones and blood cholesterol lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore encourage biliary lithiasis, which is a countereffect to UDCA used for dissolution of gallstones.

Incompatibilities: Oral suspension: Not applicable.

Keep in tight container, store below 30°C.
Oral suspension: Once opened, store in room temperature (<30°C) and use within 4 months.
Shelf life: Oral suspension: Tentative shelf life 24 months.

Cholagogues, Cholelitholytics & Hepatic Protectors

A05AA02 - ursodeoxycholic acid ; Belongs to the class of bile acids. Used in bile therapy.

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