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CSP Drug Substance Budesonide enema Date 2 Nov 2011, rev 11 Nov 425May Nov2011 2010 Supersedes Proposed Core Safety Profile Budesonide enema, tablet for rectal suspension, 2 mg (0.02 mg/mL) 1 TABLE OF CONTENTS PAGE TABLE OF CONTENTS ......................................................................................................... 2 4.3 Contraindications ..................................................................................................... 3 4.4 Special warnings and special precautions for use .................................................... 3 4.5 Interaction with other medicinal products and other forms of interaction ............... 3 4.6 Pregnancy and lactation ........................................................................................... 4 4.7 Effects on ability to drive and use machines............................................................ 4 4.8 Undesirable effects ................................................................................................... 4 4.9 Overdose .................................................................................................................. 5 2 4.3 Contraindications Hypersensitivity to budesonide or to any of the excipients. 4.4 Special warnings and special precautions for use Side effects typical of systemic corticosteroids may occur. Potential systemic effects include glaucoma Caution should be taken in patients with infections or with any other condition where corticosteroids may have unwanted effects When patients are transferred from systemic corticosteroid treatment with higher systemic effect to budesonide enema, they may have adrenocortical suppression. Some patients feel unwell in a non-specific way during the withdrawal phase, eg, 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. Replacement of high systemic effect corticosteroid treatment with Budesonide enema sometimes unmasks allergies, eg, rhinitis and eczema that were previously controlled by the systemic drug. Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. Concomitant use 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 budesonide dose could also be considered (see also section 4.5). When budesonide enema is used chronically in excessive doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. However, the dosage form - enema - and the route of administration make any prolonged overdosage unlikely. 4.5 Interaction with other medicinal products and other forms of interaction The metabolism of budesonide is primarily mediated by CYP3A4. Inhibitors of this enzyme, eg ketoconazole, itraconazole and HIV protease inhibitors can therefore increase systemic exposure to budesonide several times, see section 4.4. Since there is no data to support a dosage recommendation, the combination should be avoided. If this is not possible, the period between 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 by CYP3A4 since it has low affinity to the enzyme. 3 Concomitant treatment with CYP3A4 inducers such as carbamazepine probably reduces budesonide exposure, which may require a dose increase. Raised plasma concentrations of and enhanced effects of corticosteroids have been observed in women also treated with estrogens and contraceptive steroids, but no such effect has been observed with budesonide and concomitant intake of low dose combination oral contraceptives. 4.6 Pregnancy and lactation In pregnant animals, administration of budesonide, like other corticosteroids, is associated with abnormalities in foetal development. The relevance of these findings to humans has not been established. As with other drugs the administration of budesonide during pregnancy requires that the benefits for the mother are weighed against the risks for the foetus. Budesonide is excreted in breast milk. Maintenance treatment with inhaled budesonide (200 or 400 microg 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. 4.7 Effects on ability to drive and use machines Budesonide enema does not affect the ability to drive and use machines 4.8 Undesirable effects Tabulated list of adverse events The following definitions apply to the incidence of undesirable effects: 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). 4 Adverse drug reactions by frequency and system organ class (SOC) SOC Frequency Reaction Immune system disorders Very rare Anaphylactic reaction Endocrine disorders Rare Signs or symptoms of systemic glucocorticosteroid effects, including hypofunction of the adrenal gland Eye distorders Psychiatric disorders Unknown Uncommon Glaucoma Agitation, insomnia Gastrointestinal disorders Common Gastrointestinal disturbances, eg, flatulence, nausea, diarrhoea Skin and subcutaneous tissue disorders Common Skin reactions (urticaria, exanthema) Description of selected adverse events In rare cases signs or symptoms of systemic corticosteroid effects, including hypofunction of the adrenal gland, may occur with rectally administered corticosteroids, probably depending on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity. 4.9 Overdose Reports of acute toxicity or death following overdosage of corticosteroids are rare. Thus, acute overdosage with budesonide enema, even in excessive doses, is not expected to be a clinical problem. In the event of acute overdosage, no specific antidote is available. 5