4.1. Therapeutic indications

Cortiment is indicated in adults for:

• induction of remission in patients with mild to moderate active ulcerative colitis (UC) where 5-ASA treatment is not sufficient.

• induction of remission in patients with active microscopic colitis (MC).

4.2. Posology and method of administration

Posology

Adults

Ulcerative colitis and microscopic colitis:

The recommended daily dose for induction of remission is one 9 mg tablet in the morning, for up to 8 weeks.

When treatment is discontinued, it may be useful to gradually reduce the dose (for more details on treatment discontinuation, see section 4.4).

Paediatric population

The safety and efficacy of Cortiment tablets in children aged 0-18 years have not yet been established. No data are available, therefore the use in paediatric population is not recommended until further data become available.

Elderly

No special dose adjustment is recommended. However, experience of the use of Cortiment in the elderly is limited.

Hepatic and renal impairment population

Cortiment 9 mg was not studied in patients with hepatic and renal impairment, therefore caution should be exercised in the administration and monitoring of the product in these patients.

Method of administration

One tablet of Cortiment 9 mg is taken orally in the morning, with or without food. The tablet should be swallowed with a glass of water and must not be broken, crushed or chewed as the film coating is intended to ensure a prolonged release.

4.3. Contraindications

Hypersensitivity to the active substance, soya oil, peanut oil or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Cortiment tablets should be used with caution in patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticoids may have unwanted effects.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as Central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Reduced liver function may affect the elimination of glucocorticoids including budesonide, causing higher systemic exposure. Be aware of possible systemic side effects. Potential systemic effects include glaucoma.

When treatment is to be discontinued, it may be useful to gradually reduce the dose at the discretion of the treating physician.

Treatment with Cortiment tablets results in lower systemic steroid levels than conventional oral glucocorticoid therapy. Transfer from other steroid therapy may result in symptoms relating to the change in systemic steroid levels. Some patients may feel unwell in a non-specific way during the withdrawal phase, e.g., pain in muscles and joints. A general insufficient corticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases, a temporary increase in the dose of systemic corticosteroids is sometimes necessary.

As corticosteroids are known to have immunological effects the co-administration of Cortiment tablets is likely to reduce the immune response to vaccines.

Concomitant administration of ketoconazole or other potent CYP3A4 inhibitors should be avoided. If this is not possible, the period between treatments should be as long as possible and a reduction of the Cortiment dose could also be considered (see also section 4.5). Following significant intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased by approximately twofold. As with other drugs primarily being metabolised through CYP3A4, regular ingestion of grapefruit or grapefruit juice simultaneously with budesonide administration should be avoided (other juices such as orange juice or apple juice do not inhibit CYP3A4 activity). See also section 4.5.

Cortiment tablets contain lecithin (soya oil). If a patient is hypersensitive to peanut or soya, this medicine should not be used.

Cortiment tablets contain lactose monohydrate and should not be taken by patients with rare hereditary problems such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

The following warnings and precautions have been generally identified for corticosteroids:

• Adrenocortical suppression has been observed when patients are transferred from systemic corticosteroid treatment with higher systemic effect.

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

• Corticosteroids may cause suppression of the HPA axis and reduce the stress response. Where patients are subject to surgery or other stresses, supplementary systemic corticosteroid treatment is recommended.

• Chicken pox and measles may follow a more serious course in patients on oral glucocorticoids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If patients are infected or suspected of being infected, consider reduction or discontinuation of glucocorticosteroid treatment at the discretion of the treating physician.

• Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/behavioural effects (see section 4.8).

• Particular care is required when considering the use of systemic corticosteroids in patients with current or previous history of severe affective disorders in the patient or any first degree relatives. Replacement of high systemic effect corticosteroid treatment sometimes unmasks allergies, e.g. rhinitis and eczema that were previously controlled by the systemic drug.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Budesonide is primarily metabolized by cytochrome P450 3A4 (CYP3A4). Inhibitors of this enzyme are e.g. ketoconazole, itraconazole, HIV protease inhibitors (including cobicistat-containing products) and grapefruit juice. Co-treatment with CYP3A inhibitors is expected to increase systemic exposure to budesonide several times and the risk of systemic side effects (see section 4.4). The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects. If treatments are combined, the period between dosing of the combined treatments should be as long as possible and a reduction of the budesonide dose could also be considered. Budesonide is unlikely to inhibit other drugs metabolized via CYP3A4, since budesonide has low affinity to the enzyme.

Concomitant treatment with CYP3A4 inducers such as carbamazepine may reduce budesonide exposure, which may require a dose increase.

Corticosteroid interactions that may present a significant hazard to selected patients are those with heart glycosides (increased effect due to reduced potassium levels) and diuretics (increased elimination of potassium).

Increased plasma concentrations of and enhanced effects of corticosteroids have been observed in women also treated with oestrogens and contraceptive steroids, but no such effect has been observed with budesonide and concomitant intake of low-dose combination oral contraceptives.

Although not studied, concomitant administration of cholestyramine or antacids may reduce budesonide uptake, in common with other drugs. Therefore these preparations should not be taken simultaneously, but at least two hours apart.

At recommended doses, omeprazole does not affect the pharmacokinetics of oral budesonide, whereas cimetidine has a slight but clinically insignificant effect.

Because adrenal function may be suppressed, an ACTH stimulation test for diagnosing pituitary insufficiency might show false results (low values).

4.6. Fertility, pregnancy and lactation

Pregnancy

Data on use of inhaled budesonide in a very large number of exposed pregnancies indicate no adverse effects. Although there are no data of outcomes of pregnancies after oral administration, the bioavailability after oral administration is low. In animal experiments, at high exposures, corticosteroids proved to be harmful (see section 5.3). Cortiment should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Budesonide is excreted in breast milk.

Maintenance treatment with inhaled budesonide (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants.

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

Budesonide concentrations in infant plasma samples were all less than the limit of quantification.

Based on data from inhaled budesonide and the fact that budesonide exhibits linear PK properties within the therapeutic dosage intervals after inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the suckling child is anticipated to be low. These data support continued use of budesonide, oral and rectal administrations, during breast-feeding.

Fertility

There is no data on the effect of Cortiment on fertility in humans. There were no effects on fertility in rats after treatment with budesonide.

4.7. Effects on ability to drive and use machines

No studies on the effects of Cortiment on the ability to drive and use machines have been performed. When driving vehicles or using machines it should be taken into account that occasionally dizziness or tiredness may occur (see section 4.8).

4.8. Undesirable effects

Adverse drug reactions reported in clinical trials with Cortiment are presented in Table 1. Adverse drug reactions reported for the therapeutic class are presented in Table 2. In Phase II and III clinical trials, the incidence of adverse events for Cortiment tablets, at the recommended dose of 9 mg/day, was comparable to placebo. Most adverse events were of mild to moderate intensity and of a non-serious nature.

Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Table 1 Cortiment drug-related adverse reactions reported during clinical trials with more than one case (N=255)

MedDRA System Organ Classification

Preferred Term of Adverse Drug Reaction

Common

Uncommon

Infections and infestations

Influenza

Blood and lymphatic system disorders

Leukocytosis

Psychiatric disorders

Insomnia

Mood altered

Nervous system disorders

Headache

Dizziness

Gastrointestinal disorders

Nausea

Abdominal pain upper

Abdominal distension

Abdominal pain

Dry mouth

Dyspepsia

Flatulence

Skin and subcutaneous tissue disorders

Acne

Musculoskeletal and connective tissue disorders

Myalgia

Back pain

Muscle spasms

General disorders and administration site conditions

Fatigue

Oedema peripheral

Investigations

Blood cortisol decreased

Table 2 Events reported for the therapeutic class (intestinal anti-inflammatory agents, corticosteroids acting locally, budesonide)

MedDRA System Organ Classification

Common

Uncommon

Rare

Very Rare

Immune system disorders

Anaphylactic reaction

Endocrine disorders

Cushingoid features

Growth retardation in children*

Metabolism and nutrition disorders

Hypokalemia

Psychiatric disorders

Behavioural changes such as nervousness, insomnia and mood swings

Depression

Psychomotor hyperactivity

Anxiety

Aggression

Nervous system disorders

Tremor

Eye disorders

Cataract including subcapsular cataract

Glaucoma

Vision, blurred (see also section 4.4)

Cardiac disorders

Palpitations

Gastrointestinal disorders

Dyspepsia

Skin and subcutaneous tissue disorders

Skin reactions (urticaria, exanthema)

Ecchymosis

Musculoskeletal and connective tissue disorders

Muscle cramps

Reproductive system and breast disorders

Menstrual disorders

* Note that Cortiment is not recommended for use in children (see 4.2)

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

Paediatric population

No data available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Due to the low systemic availability of Cortiment tablets, acute overdosage even at very high doses is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.