Grinterol®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GRINTEROL® (GRINTEROL)
Composition:
Active substance: ursodeoxycholic acid;
1 hard capsule contains 250 mg of ursodeoxycholic acid;
Excipients: maize starch, silicon dioxide, magnesium stearate;
Capsule (body and cap): titanium dioxide (E 171), gelatin.
Pharmaceutical form. Hard capsules.
Main physicochemical properties: white hard gelatin capsules. Contents: white or almost white powder.
Pharmacotherapeutic group.
Agents used in the treatment of liver and biliary tract disorders. Agents used in biliary pathology. ATC code A05AA02.
Agents used in liver diseases, lipotropic agents. ATC code A05B.
Pharmacological Properties
Pharmacodynamics
A small amount of ursodeoxycholic acid is found in human bile.
After oral administration, it reduces cholesterol saturation in bile by inhibiting cholesterol absorption in the intestine and decreasing cholesterol secretion into bile. The gradual dissolution of gallstones may occur due to cholesterol dispersion and formation of liquid crystals.
According to current data, the therapeutic effect of ursodeoxycholic acid in liver diseases and cholestasis is attributed to the relative replacement of lipophilic, detergent-like toxic bile acids with hydrophilic, cytoprotective, non-toxic ursodeoxycholic acid, improvement of hepatocyte secretory function, and immunomodulatory processes.
Pediatric Use
Mucoviscidosis (Cystic Fibrosis)
The use of ursodeoxycholic acid may reduce proliferation in bile ducts, halt the progression of histological changes, and even reverse hepatobiliary abnormalities, provided that therapy is initiated at an early stage of mucoviscidosis. For optimal treatment efficacy, administration of ursodeoxycholic acid should begin immediately after confirmation of the diagnosis of mucoviscidosis.
Pharmacokinetics
After oral administration, ursodeoxycholic acid is rapidly absorbed in the small intestine and upper ileum via passive transport, and in the terminal ileum via active transport. The absorption rate typically ranges from 60% to 80%. In the liver, the bile acid undergoes nearly complete conjugation with the amino acids glycine and taurine, after which it is excreted into bile. The hepatic first-pass clearance is up to 60%.
Depending on the daily dose and the underlying liver disorder or condition, the more hydrophilic ursodeoxycholic acid accumulates in bile. Concurrently, a relative reduction in other, more lipophilic bile acids is observed.
Under the influence of intestinal bacteria, partial degradation occurs, forming 7-ketolithocholic and lithocholic acids. Lithocholic acid is hepatotoxic and causes liver parenchyma damage in some animal species. In humans, only a small amount is absorbed; this is sulfated in the liver and thereby detoxified before being excreted into bile and ultimately eliminated in feces.
The biological half-life of ursodeoxycholic acid ranges from 3.5 to 5.8 days.
Clinical characteristics.
Indications.
Dissolution of radiolucent cholesterol gallstones no larger than 15 mm in diameter in patients with a functioning gallbladder, regardless of the presence of gallstone(s) in it.
Treatment of biliary reflux gastritis.
Symptomatic treatment of primary biliary cirrhosis (PBC) in the absence of decompensated liver cirrhosis.
Treatment of hepatobiliary disorders in children aged 6 to 18 years with cystic fibrosis.
Contraindications.
Hypersensitivity to any component of the medicinal product.
Acute inflammation of the gallbladder or bile ducts.
Obstruction of bile ducts (obstruction of the common bile duct or cystic duct).
Frequent episodes of biliary colic.
Radiopaque calcified gallstones.
Impaired contractility of the gallbladder.
Failed portoenterostomy or absence of adequate bile flow in children with biliary atresia.
Interaction with other medicinal products and other forms of interaction.
The medicinal product Grinterol® must not be used concomitantly with cholestyramine, colestipol, or antacid preparations containing aluminium hydroxide and/or smectite, as these agents bind ursodeoxycholic acid in the intestine, thereby interfering with its absorption and reducing efficacy. If treatment with agents containing any of these substances is necessary, they should be administered at least 2 hours before or 2 hours after taking Grinterol® capsules.
Ursodeoxycholic acid may enhance intestinal absorption of cyclosporine. In patients receiving cyclosporine, the physician should monitor blood levels of this substance and adjust the cyclosporine dose if necessary.
In individual cases, the medicinal product Grinterol® may reduce the absorption of ciprofloxacin.
In a clinical study in healthy volunteers, concomitant administration of ursodeoxycholic acid (500 mg daily) and rosuvastatin (20 mg daily) resulted in a slight increase in rosuvastatin plasma concentration. The clinical significance of this interaction, as well as its relevance to other statins, is unknown.
It has been demonstrated that ursodeoxycholic acid reduces the maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) of the calcium antagonist nitrendipine in healthy volunteers. Careful monitoring is recommended when nitrendipine and ursodeoxycholic acid are used concomitantly. An increase in nitrendipine dosage may be required.
Furthermore, reduced therapeutic effect of dapsone has been reported.
These findings, together with in vitro data, suggest that ursodeoxycholic acid may induce cytochrome P450 3A enzymes. However, in an interaction study with budesonide, a substrate of cytochrome P450 3A, no such effect was observed.
Estrogenic hormones and lipid-lowering agents may increase hepatic cholesterol secretion and thus promote gallstone formation, which is an effect opposite to that of ursodeoxycholic acid, which is used to dissolve such stones.
Special precautions for use
Administration of Grinterol® capsules should be carried out under medical supervision.
During the first three months of treatment, liver function parameters (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transferase) should be monitored every 4 weeks, and thereafter every 3 months. This allows assessment of treatment response in patients with PBC and timely detection of liver function abnormalities, particularly in patients with advanced-stage PBC.
Treatment of cholesterol gallstones
To evaluate treatment progress and to detect early signs of stone calcification, visualization of the gallbladder (oral cholecystography) with radiographic imaging in both upright and supine positions, as well as ultrasound examination, should be performed 6–10 months after initiation of therapy.
Grinterol® should not be used if the gallbladder is not visualized on radiographic imaging, in case of stone calcification, impaired gallbladder contractility, or frequent biliary colic.
Women receiving Grinterol® for dissolution of gallstones should use an effective non-hormonal contraceptive method, since hormonal contraceptives may promote gallstone formation.
Treatment of patients with advanced-stage PBC
Very rare cases of hepatic decompensation of cirrhosis have been reported, which may partially regress after discontinuation of therapy.
In patients with PBC, symptoms may very rarely worsen at the beginning of treatment, for example, pruritus may intensify. In such cases, the dose of Grinterol® should be reduced to 1 capsule of 250 mg daily, and then gradually increased as described in the section "Dosage and administration".
If diarrhea occurs, the dose should be reduced; if diarrhea persists, treatment should be discontinued.
Use during pregnancy or breastfeeding
There are no reports of adverse effects of ursodeoxycholic acid on fertility in animals. Data on its effects on human fertility are lacking.
Data on the use of ursodeoxycholic acid in pregnant women are insufficient. Animal studies indicate reproductive toxicity in early pregnancy. Grinterol® should not be used during pregnancy except in cases of clear necessity. Women of childbearing potential should only take the drug if they are using reliable contraceptive methods.
Non-hormonal contraceptives or low-estrogen oral contraceptives are recommended. Patients receiving Grinterol® for dissolution of gallstones should use effective non-hormonal contraceptive methods, as hormonal oral contraceptives may promote gallstone formation. Pregnancy should be ruled out before starting treatment.
Based on data from several reported cases, the concentration of ursodeoxycholic acid in breast milk is very low; therefore, adverse effects in breastfed infants are unlikely.
Ability to affect reaction speed when driving or operating machinery
No effects of the medicinal product on the ability to drive or operate machinery have been observed.
Dosage and Administration
For patients weighing less than 47 kg or who have difficulty swallowing Grinterol® capsules, alternative dosage forms of ursodeoxycholic acid should be used.
For dissolution of cholesterol gallstones
Approximately 10 mg of ursodeoxycholic acid per kg of body weight (see Table 1)
Table 1
| Body weight |
Number of capsules |
| up to 60 kg 61‒80 kg 81‒100 kg over 100 kg |
2 3 4 5 |
The capsules should be swallowed whole with water, once daily in the evening before bedtime.
The capsules must be taken regularly.
The time required for dissolution of gallstones is usually 6–24 months. If no reduction in gallstone size is observed after 12 months of treatment, therapy should be discontinued.
The success of treatment should be monitored every 6 months by ultrasound or radiographic examination. Additionally, it is necessary to check whether calcification of the stones has occurred over time. If calcification occurs, treatment should be discontinued.
For the treatment of biliary reflux gastritis
1 capsule of 250 mg once daily with sufficient liquid in the evening before bedtime.
The usual course of treatment lasts 10–14 days. The duration of treatment depends on the patient's condition; therefore, the physician must decide on the treatment duration individually in each case.
For symptomatic treatment of PBC
The daily dose depends on body weight and ranges from 3 to 7 capsules (14 ± 2 mg of ursodeoxycholic acid/kg body weight).
During the first 3 months of treatment, 250 mg capsules should be taken throughout the day, dividing the daily dose into 3 doses. When liver function parameters improve, the daily dose may be taken once daily in the evening.
Table 2
| Body weight (kg) |
Daily dose (mg/kg body weight) |
Capsules |
|||
| first 3 months |
thereafter |
||||
| morning |
day |
evening |
evening (once daily) |
||
| 47–62 |
12–16 |
1 |
1 |
1 |
3 |
| 63–78 |
13–16 |
1 |
1 |
2 |
4 |
| 79–93 |
13–16 |
1 |
2 |
2 |
5 |
| 94–109 |
14–16 |
2 |
2 |
2 |
6 |
| over 110 |
2 |
2 |
3 |
7 |
|
Capsules should be swallowed whole with liquid. The regularity of intake must be maintained.
The duration of treatment with 250 mg capsules in primary biliary cirrhosis may be indefinite.
In patients with primary biliary cirrhosis, clinical symptoms may rarely worsen at the beginning of treatment; for example, pruritus may intensify. In such cases, treatment should be continued at a dose of 1 capsule of 250 mg per day, followed by gradual dose escalation (increasing the daily dose by 1 capsule weekly) until the prescribed dosing regimen is achieved.
Use in children
For children with cystic fibrosis aged 6 to 18 years, the dose is 20 mg/kg/day, divided into 2–3 doses, with subsequent increase up to 30 mg/kg/day if necessary.
Table 3
| Body weight (kg) |
Daily dose (mg/kg) |
Grinterol®, hard capsules, 250 mg |
||
| morning |
afternoon |
evening |
||
| 20–29 |
17‒25 |
1 |
‒ |
1 |
| 30–39 |
19‒25 |
1 |
1 |
1 |
| 40–49 |
20‒25 |
1 |
1 |
2 |
| 50–59 |
21‒25 |
1 |
2 |
2 |
| 60–69 |
22‒25 |
2 |
2 |
2 |
| 70–79 |
22‒25 |
2 |
2 |
3 |
| 80–89 |
22‒25 |
2 |
3 |
3 |
| 90–99 |
23‒25 |
3 |
3 |
3 |
| 100–109 |
23‒25 |
3 |
3 |
4 |
| >110 |
3 |
4 |
4 |
|
Children.
For dissolution of cholesterol gallstones, treatment of biliary reflux gastritis, and symptomatic treatment of PBC
There are no fundamental age restrictions for the use of Grinterol® in children. However, if a child weighs less than 47 kg and/or has difficulty swallowing, it is recommended to use ursodeoxycholic acid preparations in another pharmaceutical form.
For treatment of hepatobiliary disorders in cystic fibrosis
For use in children aged 6 to 18 years.
Overdose
In case of overdose, diarrhea may occur. Other symptoms of overdose are unlikely because the absorption of ursodeoxycholic acid decreases with increasing dose, and therefore most of the drug is excreted in feces.
If diarrhea occurs, the dose should be reduced; if diarrhea persists, treatment should be discontinued.
Specific antidotes are not required. Consequences of diarrhea should be managed symptomatically, with restoration of fluid and electrolyte balance.
Special patient groups
Long-term therapy with high doses of ursodeoxycholic acid (28–30 mg/kg/day) in patients with primary sclerosing cholangitis (use outside registered indication) has been associated with a higher frequency of serious adverse reactions.
Adverse reactions.
The frequency of adverse reactions is assessed as follows:
very common: >1/10;
common: >1/100 and <1/10;
uncommon: >1/1000 and <1/100;
rare: >1/10 000 and <1/1000;
very rare: <1/10 000, including individual cases.
Gastrointestinal disorders
In clinical studies, pasty stools or diarrhoea were commonly reported during treatment with ursodeoxycholic acid.
Very rarely, severe abdominal pain localized in the right hypochondrium has been observed during treatment of primary biliary cirrhosis.
Hepatobiliary disorders
Very rarely, calcification of gallstones may occur during treatment with ursodeoxycholic acid.
In treatment of advanced stages of primary biliary cirrhosis, very rarely decompensation of liver cirrhosis has been observed, which partially regressed after discontinuation of treatment.
Hypersensitivity reactions
Very rarely, allergic reactions including rash and urticaria may occur.
Shelf life. 4 years.
Do not use after the expiry date stated on the packaging.
Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of reach of children.
Packaging.
10 capsules in a blister; 5 or 10 blisters in a cardboard box.
Prescription category.
Prescription only.
Manufacturer.
JSC "Grindeks".
Manufacturer's address and place of business.
53 Krustpils Street, Riga, LV-1057, Latvia.
Marketing Authorisation Holder.
JSC "Grindeks".
Address of the Marketing Authorisation Holder.
53 Krustpils Street, Riga, LV-1057, Latvia.
Tel./Fax: +371 67083205 / +371 67083505
E-mail: [email protected]