Budesonide

The co-administration of live vaccines and glucocorticosteroids should be avoided as this is likely to reduce the immune response to vaccines. The antibody response to other vaccines may be diminished.

Compounds or drugs such as carbamazepine and rifampicin, which induce CYP3A4, might reduce the systemic but also the local exposure of budesonide at the gut mucosa. An adjustment of the budesonide dose might be necessary.

Co-treatment with potent CYP3A inhibitors such as ketoconazole, ritonavir, itraconazole, clarithromycin, cobicistat and grapefruit juice may cause a marked increase of the plasma concentration of budesonide and is expected to increase the risk of systemic adverse reactions. Therefore, concomitant use should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions, in which case patients should be monitored for systemic corticosteroid adverse reactions.

Ketoconazole 200 mg once daily orally increased the plasma concentration of budesonide (3 mg single dose) approximately 6-fold during concomitant administration. When ketoconazole was administered approximately 12 hours after budesonide, the plasma concentration of budesonide increased approximately 3-fold.

Compounds or drugs which are metabolized by CYP3A4 might be in competition with budesonide. This might lead to an increased budesonide plasma concentration if the competing substance has a stronger affinity to CYP3A4, or – if budesonide binds stronger to CYP3A4 – the competing substance might be increased in plasma and a doseadaption/reduction of this drug might be required.

In patients with severe hepatic dysfunction, treatment with inhaled budesonide can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals.

Oral administration

During treatment of patients with hepatic impairment with budesonide containing medicinal products, budesonide levels were increased. However, no systematic study investigating different levels of hepatic impairment is available. Patients with hepatic impairment should not be treated.

Budesonide is not recommended for use in patients with severe renal impairment.

The action of glycoside can be potentiated by potassium deficiency which is a potential and known adverse reaction of glucocorticoids.

Potassium excretion can be enhanced.

Elevated plasma concentrations and enhanced effects of glucocorticosteroids have been reported in women also receiving oestrogens or oral contraceptives. No such effect has been observed with budesonide and concomitant intake of low-dose combination oral contraceptives.

In theory, potential interactions with steroid-binding synthetic resins such as colestyramine, and with antacids cannot be ruled out. If given at the same time as budesonide, such interactions could result in a reduction in the effect of budesonide. Therefore these preparations should not be taken simultaneously, but at least two hours apart.

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

Caution is required in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts, family history of diabetes, family history of glaucoma, or any other condition in which glucocorticosteroids may have undesirable effects.

Respiratory administration

Most results from prospective epidemiological studies and world-wide post-marketing data have not been able to detect an increased risk for adverse effects for the foetus and newborn child from the use of inhaled budesonide during pregnancy. It is important for both foetus and mother to maintain an adequate asthma treatment during pregnancy. As with other drugs administered during pregnancy, the benefit of the administration of budesonide for the mother should be weighed against the risks to the foetus.

Oral administration

Administration during pregnancy should be avoided unless there are compelling reasons for therapy with oral budesonide. There are few data of pregnancy outcomes after oral administration of budesonide inhumans. Although data on the use of inhaled budesonide in a large number of exposed pregnancies indicate no adverse effect, the maximal concentration of budesonide in plasma has to be expected to be higher in the treatment with oral budesonide compared to inhaled budesonide. In pregnant animals, budesonide, like other glucocorticosteroids, has been shown to cause abnormalities of fetal development. The relevance of this to man has not been established.

Respiratory administration

Budesonide is excreted in breast milk. However, at therapeutic doses of budesonide no effects on the suckling child are anticipated. Budesonide can be used during breast feeding. 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 1/600^th 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 nasal, inhaled, oral and rectal administrations, at therapeutic doses of budesonide, exposure to the suckling child is anticipated to be low.

Oral administration

Budesonide is excreted in human milk (data on excretion after inhalative use is available). However, only minor effects on the breast-fed child are anticipated after oral use of budesonide within the therapeutic range. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from budesonide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of budesonide on human fertility. Fertility was unaffected following budesonide treatment in animal studies.

Budesonide has no or negligible influence on the ability to drive and use machines.

Respiratory administration

When patients are transferred from systemic corticosteroid (oral or parenteral) to Budesonide nasal spray suspension, undesirable effects outside the nasal area which were previously under control by systemic therapy e.g. allergic conjunctivitis or dermatitis, may become unmasked. They should be treated additionally if needed.

In rare cases, signs or symptoms of systemic glucocorticosteroid-side effects may occur with nasal glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity

Undesirable effects frequencies were defined as follows:

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), not known (cannot be estimated from the available data)

Paediatric population

Growth retardation has been reported in children receiving intranasal steroids. Due to the risk of growth retardation in the paediatric population, growth should be monitored.

Oral administration

Summary of the safety profile

Fungal infections in the mouth, pharynx and the oesophagus were the most frequently observed adverse reactions in clinical studies with budesonide. In the clinical studies BUL-1/EEA and BUL-2/EER, a total of 44 out of 268 patients (16.4%) exposed to budesonide experienced cases of suspected fungal infections associated with clinical symptoms, which were all of mild or moderate intensity. The total number of infections (including those diagnosed by endoscopy and histology without symptoms) was 92, occurring in 72 out of 268 patients (26.9%). Long-term treatment with budesonide of up to 3 years (48-weeks in the BUL-2/EER followed by 96-week open-label treatment) did not increase the rate of side effects including local candidiasis.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies with budesonide are listed in the table below, by MedDRA system organ class and frequency. Frequencies are defined as 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) or not known (cannot be estimated from the available data).

The following known adverse reactions of the therapeutic class (corticosteroids, budesonide) could also occur with budesonide (frequency = not known).