Cortiment tablets 9 mg No. 30

Instructions for Cortiment tablets 9 mg No. 30

Composition

active ingredient: budesonide;

1 tablet contains budesonide 9 mg;

excipients: stearic acid; lecithin (soy); microcrystalline cellulose; hydroxypropylcellulose; lactose, monohydrate; colloidal silicon dioxide; magnesium stearate;

Tablet film coating: methacrylate copolymer (type A), methacrylate copolymer (type B), talc, titanium dioxide (E 171), triethyl citrate.

Dosage form

Extended-release tablets.

Main physicochemical properties: round biconvex tablets, film-coated, white to off-white in color, engraved with “MX9” on one side.

Pharmacotherapeutic group

Anti-inflammatory drugs used in intestinal diseases. Topical corticosteroids. Budesonide. ATX code A07E A06.

Pharmacological properties

Pharmacodynamics

Mechanism of action

The exact mechanism of action of budesonide in the treatment of ulcerative colitis (UC) and microscopic colitis (MC) is not fully understood. In general, budesonide inhibits many inflammatory processes, including cytokine production, activation of inflammatory cells, and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide causes significantly less suppression of the hypothalamic-pituitary-adrenal axis and has less effect on inflammatory markers.

Data from clinical-pharmacological and pharmacokinetic studies indicate that the mechanism of action of the drug Cortiment, tablets, is based on a local action in the intestine.

Pharmacodynamic effects

Multimatrix (MMX) budesonide sustained-release tablets are characterized by a multimatrix structure and are coated with a gastro-resistant coating that dissolves in intestinal fluids with a pH greater than 7.

The protective layer protects the administered dosage form during transport through the stomach and duodenum to the lower intestine. When the protective layer dissolves, the intestinal environment comes into contact with the matrix of hydrophilic polymers, which begin to swell to form a viscous gel matrix. The solvent, penetrating the gel matrix, releases the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate during passage through the entire colon.

Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a local anti-inflammatory effect but does not reduce cortisol levels as much as systemic glucocorticoids.

Clinical efficacy

Ulcerative colitis

Two phase III randomized controlled clinical trials were conducted in 1022 adult patients with mild to moderate active UC. 255 patients received Cortiment 9 mg/day for 8 weeks. Patients enrolled were either treatment-naïve (42% of the total sample) or had failed 5-aminosalicylic acid treatment (58% of the total sample). Both studies included comparators, mesalazine and budesonide, respectively, to demonstrate assay sensitivity. In both studies, the following definition of remission was used: UCDAI (ulcerative colitis activity index) ≤ 1, rectal bleeding and stool frequency − 0, normal mucosa (no contact bleeding), and a decrease in endoscopic activity index ≥ 1.

Table 1

Effect of Cortiment 9 mg tablets on the primary endpoint

In both studies, a statistically significant difference in favor of Cortiment 9 mg tablets was observed compared to placebo, which was 10.4% and 12.9%, respectively.

5-aminosalicylic acid is the standard of care for mild to moderate UC. No direct comparative studies of Cortiment and 5-aminosalicylic acid are available. Therefore, the therapeutic value of this drug remains to be established. For some patients, the use of Cortiment as initial therapy may be beneficial.

Data on use in microscopic colitis (collagenous colitis and lymphocytic colitis) are given below. The systemic bioavailability in these diseases is similar to that described for budesonide in the drug Cortiment in the Pharmacokinetics section.

Collagenous colitis

Two randomized, double-blind, placebo-controlled induction studies of the clinical and histological effects of budesonide 9 mg/day on the course of collagenous colitis were conducted, with durations of six and eight weeks. In the first study, 23 patients were randomized to receive budesonide 9 mg/day and 22 patients to receive placebo for 6 weeks. The clinical remission rate was significantly higher (p

Data are limited for this indication. One randomized, double-blind, placebo-controlled study was conducted in 15 patients with lymphocytic colitis. Eleven patients received budesonide 9 mg/day and four patients received placebo for 8 weeks. Clinical response (defined as at least a 50% reduction in bowel movement frequency) was observed in 25% of patients in the placebo group compared with 91% of patients in the budesonide group (p = 0.03).

Children

The use of the drug Cortiment in children has not been studied.

Pharmacokinetics

Absorption

After oral administration of the conventional micronized budesonide compound, absorption appears to be complete. A significant proportion of the active substance is absorbed from the ileum and ascending colon.

The systemic availability of budesonide after a single dose of Cortiment 9 mg tablets compared to the existing form of budesonide, prolonged-release capsules 3 mg, in healthy volunteers was similar and amounted to approximately 10% with first-pass metabolism. The maximum concentration of budesonide in blood plasma is approximately 1.3-1.8 ng/ml 13-14 hours after administration. The simultaneous use of Cortiment in the form of tablets with food had no clinically significant effect on absorption. The absence of the possibility of cumulation of the drug with multiple administration has been demonstrated.

Distribution

Budesonide has a high volume of distribution (approximately 3 L/kg). Plasma protein binding is on average 85–90%.

Biotransformation

Budesonide undergoes extensive biotransformation in the liver to form metabolites with low glucocorticoid activity. The glucocorticoid activity of the main metabolites, 6-beta-hydroxybudesonide and 16-alpha-hydroxyprednisolone, does not exceed 1% of that of budesonide. The metabolism of budesonide is mainly mediated by the cytochrome P450 enzyme CYP3A.

Breeding

The rate of elimination of budesonide is limited by the extent of absorption. Budesonide has a high systemic clearance (approximately 1.2 l/min).

Children

There is no data or experience regarding the pharmacokinetics of Cortiment tablets in children.

Preclinical safety data

A combined preclinical toxicological and toxicokinetic study comparing Cortiment, extended-release tablets, with an existing extended-release formulation of budesonide in cynomolgus monkeys confirmed that Cortiment tablets have a delayed peak effect and a weaker total effect compared to the existing formulation of budesonide, while the toxicological profile of these formulations is comparable.

According to preclinical data, adverse reactions to budesonide, such as weight gain, atrophy of the adrenal glands and thymus, changes in the number of leukocytes in the blood, are less serious or similar to reactions to other glucocorticoids. As with other glucocorticosteroids, depending on the dose, duration of use and associated diseases, these reactions may also be observed in humans.

Budesonide does not affect fertility in rats. In pregnant rats and rabbits, budesonide, like other glucocorticosteroids, caused foetal death and foetal abnormalities (reduced litter size, intrauterine growth retardation and skeletal anomalies). Some glucocorticoids have been shown to cause cleft palate in animals. The relevance of these findings to humans has not been established (see also section "Use during pregnancy and lactation").

Budesonide was not mutagenic in a number of in vitro and in vivo studies. A slight increase in basophilic inclusions in the liver was observed in long-term studies of budesonide in rats, and in carcinogenicity studies an increase in the incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumors (in female rats) was observed. These tumors are probably caused by the action of specific steroid receptors, an increase in metabolic load and anabolic effects on the liver; these effects have also been observed in studies of other glucocorticosteroids in rats and are therefore class-specific effects in this species.

Indication

Cortiment is indicated for the induction of remission in adult patients with mild to moderate active ulcerative colitis (UC) when treatment with 5-aminosalicylic acid is inadequate, and for the induction of remission in patients with active microscopic colitis (MC).

Contraindication

Hypersensitivity to budesonide, soy, peanut or any of the excipients of the drug.

Interaction with other medicinal products and other types of interactions

Budesonide is primarily metabolised by cytochrome P450 3A4 (CYP3A4). Inhibitors of this enzyme, such as ketoconazole, itraconazole, HIV protease inhibitors (including cobicistat-containing products) and grapefruit juice, may increase the systemic exposure of budesonide several-fold and increase the risk of systemic side effects (see section 4.4). This combination should be avoided unless the benefit outweighs the increased risk of systemic side effects of corticosteroids, in which case patients should be monitored for systemic side effects of corticosteroids. If combination therapy is used, the interval between doses of the combination should be as long as possible; a reduction in the dose of budesonide should also be considered. The likelihood that budesonide will inhibit other drugs that are metabolized by CYP3A4 is low, as budesonide has a low affinity for this enzyme.

Concomitant treatment with CYP3A4 inducers such as carbamazepine may weaken the effect of budesonide, therefore an increase in dose may be necessary.

Drugs that may pose significant risks to individual patients when interacting with corticosteroids include cardiac glycosides (increased effects due to decreased potassium levels) and diuretics (increased potassium excretion).

When used simultaneously with estrogens or oral contraceptives in women, an increase in plasma concentrations and enhanced action of corticosteroids was observed, but this effect was not observed with the simultaneous use of budesonide and combined low-dose oral contraceptives.

Although studies are lacking, concomitant use with cholestyramine or antacids may reduce the absorption of budesonide, as with other drugs. Therefore, these drugs should not be taken simultaneously, but at least two hours apart.

At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide, while cimetidine has a minor effect that is not clinically significant.

Due to the possibility of adrenal suppression, adrenocorticotropic hormone (ACTH) stimulation tests to diagnose pituitary insufficiency may show false results (low levels).

Application features.

Cortiment should be administered with caution to patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer disease, glaucoma or cataracts, a family history of diabetes or glaucoma, or any other condition in which the use of glucocorticoids may have undesirable effects.

Visual disturbances may occur with systemic and topical corticosteroids. If a patient presents with symptoms such as blurred vision or other visual disturbances, it is recommended that they be referred to an ophthalmologist for evaluation of the possible cause of these disturbances, which may be due to cataracts, glaucoma, or a rarer condition such as central serous chorioretinitis, which has been reported with systemic and topical corticosteroids.

Decreased liver function may affect the excretion of glucocorticoids, including budesonide, resulting in increased systemic exposure. The possibility of systemic adverse reactions should be considered. Possible systemic adverse reactions include glaucoma.

In the event of discontinuation of treatment, a gradual dose reduction under medical supervision may be recommended.

Treatment with Cortiment results in a greater reduction in systemic steroid levels than with conventional oral glucocorticoids. Switching from other steroid therapy may result in symptoms related to changes in systemic steroid levels. During the withdrawal period, some patients may experience non-specific symptoms such as muscle and joint pain. If, in rare cases, symptoms such as fatigue, headache, nausea and vomiting occur, a general lack of corticosteroid effect should be suspected. In such cases, a temporary increase in the dose of systemic corticosteroids may be necessary.

Since corticosteroids are known to have immunological effects, concomitant use of Cortiment may result in a decreased immune response to vaccines.

The use of the drug Cortimen may lead to positive results in doping tests. The use of this drug for doping purposes may be dangerous to health.

Cortimen contains lecithin (from soybean oil). If the patient is hypersensitive to peanut or soybean, this medicine should not be used.

Cortiment tablets contain lactose monohydrate, so the drug should not be prescribed to patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

General warnings and precautions when using corticosteroids:

Adrenocortical suppression has been observed when patients are transferred from systemic corticosteroid therapy to more potent systemic corticosteroids.

· Suppression of the inflammatory response and immune system increases susceptibility to infections.

· Corticosteroids may cause suppression of the hypothalamic-pituitary-adrenal axis and a decrease in the stress response. If patients are undergoing surgery or other stress, additional treatment with systemic corticosteroids is recommended.

· In patients receiving oral glucocorticoids, chickenpox and measles may be more severe. Special attention should be paid to prophylaxis in patients who have not previously had these diseases. If patients are infected or suspected of infection, consideration should be given to discontinuing treatment or reducing the dose of glucocorticosteroids at the discretion of the physician.

Systemic adverse reactions to steroids may occur, especially when given in high doses and for prolonged periods. These reactions may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataracts, glaucoma and, very rarely, a wide range of mental/behavioural disturbances (see section 4.8).

· Particular caution should be exercised when considering the use of systemic corticosteroids in patients with a history (of the patient himself or any first-degree relatives) of severe affective disorders.

· Switching treatment to highly potent systemic corticosteroids sometimes unmasks allergic reactions such as rhinitis and eczema that were previously controlled by the systemic drug.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of inhaled budesonide in a large number of women during pregnancy indicate no adverse reactions. Although there are no data on pregnancy outcomes after oral administration, the bioavailability after such administration is low. In animal experiments, corticosteroids have been shown to be harmful at high doses (see section 5.3). Cortiment should be used during pregnancy only if the expected benefit to the mother justifies the potential risk to the fetus.

Breastfeeding period

Budesonide passes into breast milk.

Maintenance treatment with inhaled budesonide (200 to 400 mcg twice daily) in asthmatic women who are breastfeeding results in inadvertently low systemic exposure to budesonide in breastfed infants.

In a pharmacokinetic study, the estimated daily dose in infants was 0.3% of the maternal daily dose for both dose levels, and the mean plasma concentration in infants was estimated to be 1/600 of the concentration observed in maternal plasma, suggesting complete oral bioavailability in the infant.

Plasma concentrations of budesonide in infants were below the limit of detection. Based on data obtained with inhaled budesonide and the linear pharmacokinetics within the therapeutic dose range, exposure in breastfed infants is expected to be low after oral and rectal administration of therapeutic doses of budesonide. These data support the continued use of oral and rectal budesonide during breast-feeding.

Fertility

There are no data on the effect of Cortiment on human fertility. Budesonide has not been shown to have any effect on rat fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

Studies on the ability of Cortiment to affect the speed of reaction when driving or operating other mechanisms have not been conducted. When driving or operating other mechanisms, it should be taken into account that dizziness or increased fatigue may occasionally occur (see section "Adverse reactions").

Method of administration and doses

Dosage

Adults

The recommended daily dose for induction of remission in ulcerative colitis and microscopic colitis is 1 tablet of 9 mg in the morning, the duration of the treatment course is up to 8 weeks.

When stopping treatment, it may be useful to gradually reduce the dose (for more information on stopping treatment, see section 4.4).

The safety and efficacy of Cortiment in children under the age of 18 have not been studied. Due to the lack of information, the use of the drug in pediatric practice is not recommended until additional data are obtained.

Elderly patients

No dose adjustment is required, but experience with the use of Cortiment in elderly patients is limited.

Patients with impaired liver and kidney function

The use of Cortiment 9 mg has not been studied in patients with impaired liver and kidney function, therefore, it is necessary to prescribe the drug with caution and carefully monitor the condition of patients in this group.

Method of application

Take 1 tablet of Cortiment 9 mg orally in the morning, on an empty stomach or with food. The tablet should be washed down with a glass of water; it should not be broken, crushed or chewed, as the film coating that covers the tablet provides a delayed release.

Children

The safety and efficacy of Cortiment in children (under 18 years of age) have not been studied, therefore the drug is not used in pediatric practice.

Overdose

Due to the low systemic availability of Cortiment tablets, there is no reason to believe that acute overdose, even at very high doses, will result in an acute clinical crisis.

There is no specific antidote for acute overdose.

Treatment consists of supportive and symptomatic therapy.

Adverse reactions

Information on adverse reactions during clinical trials is presented in Table 2. Information on adverse reactions related to the therapeutic class of the drug is presented in Table 3. In clinical trials of phases II and III, the frequency of adverse reactions with the use of Cortiment, tablets, at the recommended dose of 9 mg/day was comparable to placebo. Most adverse reactions were mild or moderate in intensity.

Classification of the frequency of adverse reactions: very common (≥ 1/10); common (≥ 1/100,

Table 2

Information on adverse reactions of Cortiment during clinical trials observed more than once (n = 255)

Table 3

Adverse reactions related to the therapeutic class of the drug (anti-inflammatory intestinal drugs, topical corticosteroids, budesonide)

*Note: Cortiment is not recommended for use in children (see section “Method of administration and dosage”).

Most of the listed adverse reactions are also characteristic of other systemic glucocorticoids. Adverse reactions typical of systemic glucocorticosteroids may occur (e.g. signs of Cushing's syndrome and growth retardation). Such adverse reactions depend on the dose, duration of treatment, concomitant or previous use of corticosteroids, or individual sensitivity.

Children

No data.

Reporting adverse reactions after the registration of a medicinal product is important. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

Store out of the reach of children at a temperature not exceeding 30 °C.

Packaging

10 tablets in a blister, 3 blisters in a package.

Vacation category

According to the recipe.

Producer

Cosmo S.P.A., Italy.

Location of the manufacturer and address of its place of business

Via C. Colombo, 1, 20045 Lainate (MI), Italy.