LITOFF

L I T O F F
“450 mg tablets” 20 prolonged-release tablets
“300 mg tablets” 20 tablets
“450 mg tablets” 20 tablets
Ursodeoxycholic Acid

THERAPEUTIC CATEGORY
Bile acid-based preparations.

THERAPEUTIC INDICATIONS
Qualitative or quantitative disorders of bile formation, including conditions with cholesterol-supersaturated bile, to prevent the formation of cholesterol stones or to create favorable conditions for dissolution when radiolucent gallstones are already present; specifically, gallstones in a functioning gallbladder and residual or recurrent stones in the common bile duct following biliary tract surgery. Biliary dyspepsia.

CONTRAINDICATIONS
The product is also contraindicated in pregnant women and in patients with active gastric or duodenal ulcer.

Ursodeoxycholic acid must not be used in patients with:
a. Acute inflammation of the gallbladder or biliary tract
b. Biliary tract obstruction (common or cystic duct obstruction)
c. Frequent biliary colic
d. Calcified, radiopaque gallstones
e. Reduced gallbladder motility
f. Hypersensitivity to bile acids or to any of the excipients.

SUITABLE PRECAUTIONS FOR USE
Monitoring bile composition to confirm cholesterol desaturation represents an important predictive factor for favorable treatment outcome. In patients with frequent biliary colic, biliary infections, severe pancreatic disorders, or intestinal conditions that may alter the enterohepatic circulation of bile acids (e.g., ileal resection or stoma, regional ileitis, etc.), use of the product should be avoided. In patients undergoing treatment for gallstone dissolution, efficacy should be monitored by cholecystographic or ultrasonographic examinations every 6 months.

Prior to initiating long-term treatment, baseline liver transaminases and alkaline phosphatase should be checked.

INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, including those without a prescription.

Avoid concomitant use with substances that inhibit intestinal absorption of bile acids, such as cholestyramine, and with drugs that increase biliary cholesterol excretion (estrogens, hormonal contraceptives, certain lipid-lowering agents).

Ursodeoxycholic acid must not be co-administered with cholestyramine, colestipol, or antacids containing aluminum hydroxide and/or smectite (aluminum oxide), as these bind ursodeoxycholic acid in the intestine and inhibit its absorption and efficacy. If use of these substances is necessary, they should be taken at least 2 hours before or after ursodeoxycholic acid.

Ursodeoxycholic acid may affect the intestinal absorption of cyclosporine. In patients receiving cyclosporine, blood levels should be monitored by the physician and the cyclosporine dose adjusted if necessary.

In isolated cases, ursodeoxycholic acid may reduce the absorption of ciprofloxacin.

In a clinical study in healthy volunteers, concomitant administration of UDCA (500 mg/day) and rosuvastatin (20 mg/day) resulted in a slight increase in plasma levels of rosuvastatin. The clinical significance of this interaction, particularly with other statins, is unknown.

Ursodeoxycholic acid has been shown to reduce the peak plasma concentration (Cmax) and area under the curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Close monitoring is recommended when nitrendipine and ursodeoxycholic acid are used concomitantly. An increase in nitrendipine dosage may be necessary. An interaction resulting in reduced therapeutic effect of dapsone has also been reported. These observations, together with in vitro evidence, suggest a potential induction of cytochrome P450 3A enzymes by ursodeoxycholic acid. However, in a well-designed interaction study with budesonide, a known substrate of cytochrome P450 3A, no enzyme-inducing effect was observed.

Estrogens and cholesterol-lowering agents such as clofibrate increase hepatic cholesterol secretion and may therefore promote gallstone formation, an effect opposite to that of ursodeoxycholic acid used for stone dissolution.

SPECIAL WARNINGS
Prior to initiating long-term dissolution therapy, baseline transaminase and alkaline phosphatase levels should be checked.

Ursodeoxycholic acid must 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, and thereafter every 3 months. This monitoring allows identification of responsive and non-responsive patients in primary biliary cirrhosis treatment and may also facilitate early detection of potential liver deterioration, particularly in patients with advanced primary biliary cirrhosis.

When used for dissolution of cholesterol stones:
To confirm therapeutic improvement and to temporarily identify stone calcification, depending on stone size, the gallbladder should be visualized (oral cholecystography) with overall and occluded duct views in upright and supine positions (ultrasound control) 6–10 months after starting treatment.

Ursodeoxycholic acid should not be used if gallbladder visualization by X-ray imaging is not possible, or in cases of calcified stones, impaired gallbladder contractility, or frequent episodes of biliary colic.

Women taking LITOFF for gallstone dissolution must use an effective non-hormonal contraceptive method, as hormonal oral contraceptives may increase the risk of gallstone formation (see sections 4.5 and 4.6).

When used for treatment of advanced-stage primary biliary cirrhosis:
Very rarely, hepatic decompensation has been observed, which partially regressed after discontinuation of treatment.

In rare cases, clinical symptoms in patients with PBC (primary biliary cirrhosis) may worsen at the beginning of treatment; for example, pruritus may increase. In such cases, the dose of LITOFF should be reduced to 250 mg per day and then gradually increased again.

In case of diarrhea, the dose should be reduced; if diarrhea persists, treatment should be discontinued.

FERTILITY, PREGNANCY AND LACTATION
Consult your doctor or pharmacist before taking any medicine.

Animal studies have not shown effects of ursodeoxycholic acid on fertility. Human data on effects on fertility following treatment with ursodeoxycholic acid are not available.

Data on the use of ursodeoxycholic acid in pregnant women are lacking or limited in number. Animal studies have shown reproductive toxicity during the first phase of gestation.

LITOFF must not be used during pregnancy unless clearly necessary.

Women of childbearing potential should only be treated if they are using a reliable contraceptive method: non-hormonal or low-estrogen oral contraceptives are recommended. However, in women taking ursodeoxycholic acid for gallstone dissolution, use of an effective non-hormonal contraceptive method is advised, as hormonal oral contraceptives may increase the risk of gallstone formation. Pregnancy should be ruled out before starting treatment.

Based on limited documented cases in breastfeeding women, levels of ursodeoxycholic acid are very low and adverse reactions in breastfed infants are unlikely.

Effects on ability to drive and use machines
Ursodeoxycholic acid does not alter or alters only negligibly the ability to drive vehicles or operate machinery.

Important information on some excipients
This medicine contains lactose. Therefore, if your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.

DOSAGE, ADMINISTRATION AND DURATION
For long-term use to reduce the lithogenic properties of bile, the daily dosage is 5–10 mg/kg. In most cases, the daily dose ranges between 300 and 600 mg, equivalent to 1–2 tablets of 300 mg twice daily (morning and evening) or one 450 mg tablet once daily. To maintain conditions favorable for dissolution of existing stones, treatment should last at least 4–6 months, up to 12 months or longer, continuously, and should continue for 3–4 months after radiological or ultrasonographic disappearance of the stones.

Treatment should not exceed 2 years. For dyspeptic syndromes and maintenance therapy, doses of 300 mg daily, divided into 2–3 doses, are generally sufficient.

Dosages may be adjusted at the physician’s discretion; the excellent tolerability of the product allows even significantly higher doses to be used. Tablets should preferably be taken during or after meals. Pediatric use is not indicated.

OVERDOSE
In case of accidental ingestion/overdose of LITOFF, contact your doctor immediately or go to the nearest hospital.

If you have any doubts about the use of LITOFF, consult your doctor or pharmacist.

No cases of overdose exceeding 4 g/day have been reported (a dose that has proven well tolerated).

In case of accidental ingestion of highly excessive doses of ursodeoxycholic acid, standard measures for intoxication should be implemented, and cholestyramine administered, as it is capable of binding bile acids.

Diarrhea may occur in cases of overdose. Generally, other overdose symptoms are unlikely, as absorption of ursodeoxycholic acid decreases with increasing dose, leading to greater fecal excretion.

No specific countermeasures are required; consequences of diarrhea should be treated symptomatically with fluid and electrolyte replacement.

Additional information on special patient populations:
Long-term, high-dose therapy with UDCA (28–30 mg/kg/day) in patients with primary sclerosing cholangitis (off-label use) has been associated with higher rates of serious adverse events.

UNDESIRABLE EFFECTS
Like all medicines, LITOFF can cause side effects, although not everyone experiences them.

Tolerability at recommended doses is generally good. Occasionally, bowel irregularities have been reported, which usually resolve during continued treatment.

For classification of adverse reaction frequencies, the following convention is used:
Very common (≥ 1/10),
Common (≥ 1/100 to < 1/10),
Uncommon (≥ 1/1000 to < 1/100),
Rare (≥ 1/10,000 to < 1/1000),
Very rare (< 1/10,000),
Not known (frequency cannot be estimated from available data)

Gastrointestinal disorders:
In clinical studies, soft stools or diarrhea are commonly reported during therapy with ursodeoxycholic acid.

Very rarely, severe right upper quadrant abdominal pain has occurred during treatment for primary biliary cirrhosis.

Hepatobiliary disorders:
In very rare cases, gallstone calcification has occurred during treatment with ursodeoxycholic acid. During treatment of advanced primary biliary cirrhosis, hepatic decompensation has very rarely been observed, which partially regressed after treatment discontinuation.

Skin and subcutaneous tissue disorders:
Very rarely, urticaria may occur.

Following the instructions in this leaflet reduces the risk of adverse effects.

If any of the side effects worsens or if you notice any side effect not listed in this leaflet, inform your doctor.

EXPIRY AND STORAGE
Expiry date: See the date on the packaging.
This date refers to the product stored unopened and under proper storage conditions.
Warning: Do not use the medicine after the expiry date stated on the packaging.

Keep the medicine out of the reach and sight of children.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This helps protect the environment.

COMPOSITION
300
Each tablet contains:
Active substance: ursodeoxycholic acid 300 mg
Excipients: lactose, sodium starch glycolate, gum arabic, talc, magnesium stearate, pregelatinized starch.

450
Each tablet contains:
Active substance: ursodeoxycholic acid 450 mg
Excipients: lactose, starch, gum arabic, talc, magnesium stearate.

450 retard
Each prolonged-release tablet contains:
Active substance: ursodeoxycholic acid 450 mg
Excipients: hypromellose methocel K15M, hypromellose methocel K100M, microcrystalline cellulose, lactose, polyvinylpyrrolidone, talc, magnesium stearate.

PHARMACEUTICAL FORM AND PACKAGING
20 tablets of 300 mg, divisible
20 tablets of 450 mg
20 prolonged-release tablets of 450 mg

MARKETING AUTHORIZATION HOLDER
I.B.N. SAVIO S.r.l. - Via del Mare n. 36 – Pomezia (RM)

MANUFACTURER
Istituto Biochimico Nazionale SAVIO S.r.l. - Via del Mare n. 36 – Pomezia (RM)
For 300 mg tablets and 450 mg prolonged-release tablets also:
Special Product’s Line S.p.A., Strada Paduni n. 240 – Anagni (FR)