Reports of acute toxicity or death following overdosage of glucocorticosteroids are rare. Thus, acute overdosage with Nalator CR Capsules even in excessive 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.
Chronic overdosage may lead to systemic corticosteroid effects, such as Cushingoid features. If such changes occur, the dose of Nalator CR Capsules should be gradually reduced until treatment is discontinued, in accordance with normal procedures for the discontinuation of prolonged oral glucocorticosteroid therapy.
None applicable.
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); Not Known (cannot estimate from the available data).
Adverse drug reactions by frequency and system organ class (SOC)
| SOC | Frequency | Reaction |
| Immune system disorders | Very Rare | Anaphylactic reaction |
| Endocrine disorders | Common | Cushingoid features |
| Very Rare | Growth retardation | |
| Metabolism and nutrition disorders | Common | Hypokalemia |
| Psychiatric disorders | Common | Behavioural changes such as nervousness, insomnia, mood swings and depression |
| Uncommon | Anxiety | |
| Rare | Aggression | |
| Nervous system disorders | Uncommon | Tremor, psychomotor hyperactivity |
| Eye disorders | Rare | ) |
| Cardiac disorders | Common | Palpitations |
| Gastrointestinal disorders | Common | Dyspepsia |
| Skin and subcutaneous tissue disorders | Common | Skin reactions (urticaria, exanthema) |
| Rare | Ecchymosis | |
| Musculoskeletal and connective tissue disorders | Common | Muscle cramps |
| Reproductive system and breast disorders | Common | Menstrual disorders |
Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.
Description of selected adverse events
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.
In clinical studies, at recommended doses, the incidence of adverse events was comparable to placebo.
Clinical studies showed the frequency of steroid associated side effects for Nalator CR Capsules to be approximately half that of conventional prednisolone treatment, at equipotent doses. In studies of patients with active disease, receiving Nalator 9 mg daily, the incidence of adverse events was comparable to placebo. Very rarely a wide range of psychiatric/ behavioural effects may occur, when systemic steroids are prescribed at high doses and for prolonged periods.
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.
Preclinical data revealed no special hazard for humans in the therapeutic dose range based on studies of chronic toxicity, genotoxicity and carcinogenicity.
Glucocorticoids, including Nalator, have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at the recommended dose levels.
Preclinical investigations on dogs have shown that Nalator 2mg rectal foam is well tolerated locally.
Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. These steroid effects might also be of relevance in man.
Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.
A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies there was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.
In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows that there are no indications that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
A preclinical toxicology and toxicokinetic bridging study, comparing Nalator tablets with an existing prolonged release budesonide formulation (Entocort® EC 3 mg capsules, AstraZeneca) in cynomolgous monkeys has confirmed that Nalator tablets result in a delayed peak exposure and reduced total exposure compared to the existing formulation of budesonide, while maintaining a superimposable toxicological profile.
Preclinical data have shown that budesonide produces effects less severe or similar to other glucocorticoids, such as weight increase, atrophy of the adrenal glands and thymus and effects on the leucocyte count. As with other glucocorticosteroids, and dependent on the dose and duration and the diseases concerned, these steroid effects may also be relevant in man.
Budesonide had no effect on fertility in rats.).
Budesonide had no mutagenic effects in a number of in vitro and in vivo tests. A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (in female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from rat studies with other glucocorticosteroids and therefore represent a class effect in this species.
The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclomethasone dipropionate, flucinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than or similar to those observed after administration of the other glucocorticosteroids e.g. decreased body weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary heptocellular neoplasms in man. Budesonide has been used successfully in the treatment of seasonal allergic rhinitis for several years.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behavioural exposures below the teratogenic dose range.
Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.
Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.
The toxicity of Nalator CR Capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys in doses up to 5 mg/kg after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, neither at gross pathology nor in the histopathological examination.
Crohn's disease - Induction of remission in patients with mild to moderate active Crohn's disease affecting the ileum and/or the ascending colon.
Microscopic colitis - Induction of remission in patients with active microscopic colitis
Pharmacotherapeutic group: Other drugs for obstructive airways diseases, inhalant, Glucocorticoids
ATC code: R03 BA 02
Nalator is a glucocorticosteroid with a powerful local anti-inflammatory action.
Mechanism of action
The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of Nalator, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone.
Clinical efficacy and safety
A clinical trial with asthma patients in which inhaled and oral Nalator was compared with placebo, showed statistically significant effects of inhaled Nalator, but not of oral Nalator. The therapeutic effect of normally used doses of inhaled Nalator may therefore chiefly be explained by a direct effect on the airways.
Nalator has demonstrated an anti-anaphylactic and anti-inflammatory effect in challenge tests in experimental animals and in patients. This effect has manifested itself as reduced bronchial obstruction in both the immediate and the later allergic reaction.
It was also demonstrated that Nalator reduces the airways' reactivity to histamine and metacholine in hyperreactive patients. Treatment with inhaled Nalator has been used to effectively prevent exercise-induced asthma.
Influence on plasma cortisol concentration:
Studies in healthy volunteers with inhaled Nalator have shown dose-related effect on plasma and urinary cortisol. At recommended doses, inhaled Nalator causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test. No clinically relevant changes in the plasma cortisol values or response to ACTH stimulation were observed when Nalator was given in doses up to 1600 µg daily for 3 months to adults and up to 800 µg daily to children. Long-term monitoring for up to 52 weeks confirmed that the HPA axis was not suppressed.
Paediatric population
Clinical - asthma
The efficacy of Nalator nebuliser suspension has been evaluated in a large number of studies, and it has been shown that Nalator nebuliser suspension is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.
Clinical - croup
A number of studies in children with croup have compared Nalator nebuliser suspension with placebo. Examples of representative studies evaluating the use of Nalator for the treatment of children with croup are given below.
Efficacy in children with mild to moderate croup
A randomized, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Nalator nebuliser suspension improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Nalator nebuliser suspension (2 mg) or placebo was given followed by either Nalator 1 mg or placebo every 12 hours. Nalator nebuliser suspension statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.
Efficacy in children with moderate to severe croup
A randomized, double-blind, placebo-controlled study compared the efficacy of Nalator nebuliser suspension and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Nalator 2 mg nebuliser suspension or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Nalator nebuliser suspension and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Nalator nebuliser suspension group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Both asthma and inhaled glucocorticosteroids may affect the growth in length. The effect of Nalator Nebuliser Suspension on the growth in length was studied in 519 children (from 8 months to 9 years) in three prospective, randomised, open, non-blinded studies. The studies did not show any significant difference in the growth in length of children treated either with Nalator Nebuliser Suspension or with conventional asthma therapy. Two studies (N = 239 and 72 patients, respectively) showed 7 mm and 8 mm greater growth after one year of treatment with Nalator Nebuliser Suspension compared with traditional asthma therapy (not statistically significant), while one study (N = 208) showed a growth in length that after one year was 8 mm smaller in the Nalator Nebuliser Suspension group than in the group of conventional asthma treatment (statistically significant difference).
Pharmacotherapeutic group: Intestinal antiinflammatory agents, corticosteroids acting locally
ATC code: A07EA06
The exact mechanism of action of budesonide in the treatment of ulcerative colitis/procto-sigmoiditis is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At a dosage of 2 mg budesonide, applied rectally, budesonide leads to practically no suppression of the hypothalamus-hypophysis-adrenal cortex axis.
Nalator 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02
Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
Topical anti-inflammatory effect
The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.
Onset of effect
After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity
Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients.
Exercise-induced asthma
Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
Growth
In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.
Influence on plasma cortisol concentration
Studies in healthy volunteers with Nalator Turbohaler have shown dose-related effect on plasma and urinary cortisol. At recommended doses, Nalator Turbohaler causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test.
Paediatric population
Clinical - asthma
The efficacy of Nalator Respules has been evaluated in a large number of studies, and it has been shown that Nalator Respules is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.
Clinical - croup
A number of studies in children with croup have compared Nalator Respules with placebo. Examples of representative studies evaluating the use of Nalator Respules for the treatment of children with croup are given below.
Efficacy in children with mild to moderate croup
A randomised, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Nalator Respules improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Nalator Respules (2 mg) or placebo was given followed by either Nalator Respules 1 mg or placebo every 12 hours. Nalator Respules statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.
Efficacy in children with moderate to severe croup
A randomised, double-blind, placebo-controlled study compared the efficacy of Nalator Respules and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Nalator Respules 2 mg or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Nalator Respules and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Nalator Respules group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02.
Topical anti-inflammatory effect
The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.
Onset of effect
After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity
Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Exercise-induced asthma
Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
Growth
In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.
Paediatric Population
Slit lamp examinations were performed in 157 children (5-16 years old), treated with an average daily dose of 504 μg for 3-6 years. Findings were compared with 111 age-matched asthmatic children. Inhaled budesonide was not associated with an increased occurrence of posterior subcapsular cataract.
Influence on plasma cortisol concentration
Studies in healthy volunteers with Nalator have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Nalator, causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Corticosteroids acting locally
ATC code: A07E A06
Mechanism of action
The exact mechanism of action of budesonide in the treatment of UC is not fully understood. In general, budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
Data from clinical pharmacology and pharmacokinetic studies indicate that the mode of action of Nalator tablets is based on a local action in the gut.
Pharmacodynamic effects
MMX extended release technology is characterised by a multi-matrix structure covered by a gastro-resistant coating that dissolves in intestinal fluids having a pH greater than 7.
When the dosage form is administered, the gastro-protective layer protects the dosage form during transit through the stomach and duodenum up to the lower part of the intestine. When the protective layer is lost, the intestinal fluid then comes into contact with the hydrophilic matrix polymers, which start to swell until a viscous gel matrix is formed. The solvent that penetrates into the gel matrix dissolves the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate throughout the colon.
Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a topical anti-inflammatory activity, but does not reduce cortisol levels to the same extent as systemic glucocorticoids.
Clinical efficacy
Two randomised, controlled phase III clinical trials including 1022 patients with mild to moderate active UC have been performed in adult patients. Two hundred fifty five (255) patients were treated for 8 weeks with Nalator 9 mg per day. Patients included were either treatment naïve (42% ITT) or had failed on 5-ASA (58% ITT). Both studies included a reference arm, mesalazine (Asacol) and budesonide (Entocort), respectively to show assay sensitivity. The definition of remission applied in both studies was UCDAI score of ≤1, with 0 score for rectal bleeding and stool frequency, normal mucosa (no friability) and >1 point reduction in endoscopy score.
Effect of Nalator 9mg tablet on Primary Endpoint:
| Study | Nalator 9 mg Remission (%) | Placebo Remission (%) | P= |
| Study CB-01-02/01 | 17.9 | 7.4 | 0.0143 |
| Study CB-01-02/02 | 17.4
| 4.5
| 0.0047 |
Statistical difference versus placebo was reached for Nalator 9 mg for both studies and the difference versus placebo was 10.4% and 12.9% respectively.
5-ASA is the Standard of Care for treatment of mild to moderate disease. Results of a head to head comparison with Nalator and 5-ASA were not available. Therefore, the place in the therapeutic work-up remains to be established. Some patients may benefit from treatment initially with Nalator.
Paediatric Population
Nalator was not studied in the paediatric population.
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05
Budesonide is a non-halogenated glucocorticosteroid with a high local anti-inflammatory action within the respiratory tract.
Pharmacotherapeutic group: Corticosteroids acting locally.
ATC code: A07EA06
Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
The exact mechanism of budesonide in the treatment of Crohn's disease is not fully understood.
Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Nalator CR Capsules is based, at least partly, on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
At recommended doses, Nalator CR Capsules caused significantly less effect than prednisolone 20-40 mg daily on morning plasma cortisols; on 24 hour plasma cortisol (AUC 0-24 h) and on 24 hour urine cortisol levels.
ACTH tests have shown Nalator CR Capsules to have significantly less effect than prednisolone on adrenal functions.
Paediatric population
HPA axis function. At recommended doses, Nalator CR Capsules cause significantly less effect than prednisole 20-40 mg daily on morning plasma cortisol, on 24-hour plasma cortisol (AUC 0-24 h) and on 24-hour urine cortisol. Also ACTH tests have shown that Nalator CR Capsules, compared with prednisolone, have significantly less impact on the adrenal function. Children with Crohn's disease have a slightly higher systemic exposure and cortisol suppression than adults with Crohn's disease.
Long-term studies have not been performed in children treated with Nalator CR Capsules. In a study evaluating the effect of Nalator CR Capsules on cortisol suppression in 8 children (range 9-14 years) and 6 adults , the oral administration of 9 mg Nalator CR Capsules for 7 days induced a mean cortisol suppression (± SD) of 64% (±18%) in children and 50% (±27%) in adults with respect to baseline values. No clinically relevant findings in terms of safety have been reported. (Study 08-3044)
A study performed in children with mild to moderate Crohn's disease (CDAI > 200) compared the activity of Nalator CR Capsules at the dose of 9 mg once daily with that of prednisolone, administered at tapering doses, starting from 1 mg/kg. 22 patients were treated with Nalator CR Capsules and 26 patients were treated with the reference drug prednisolone. After 8 weeks of treatment, 70.8% of patients treated with prednisolone reached the endpoint (CDAI ≤ 150), as compared to 54.5% of subjects treated with Nalator CR Capsules, the difference was not statistically significant (p = 0.13). In the course of the study, adverse events were observed in 96% of patients treated with prednisolone and 91% of patients treated with Nalator CR Capsules. The nature of these adverse events was similar in both study arms, but the incidence of glucocorticoid-related side-effects (such as acne and moon face) was lower in patients treated with Nalator CR Capsules. (Study SD-008-3037)
Study D9422C0001 was an open-label, uncontrolled study designed to evaluate Nalator in 108 pediatric patients (children and adolescents aged 5 to 17 years) diagnosed with mild to moderate Crohn's disease of the ileum and/or ascending colon. The median duration of treatment exposure of Nalator of 58 days (range: 5 days to 90 days). Patients were dosed with oral Nalator once daily according to bodyweight, patients weighing ≤25 kg received 6 mg once daily for 8 weeks; patients weighing >25 kg received 9 mg once daily for 8 weeks. During the 8 weeks of treatment there was a reduction in the mean (±SD) PCDAI score from 19.1 (±10.1) to 9.1 (±8.5), indicating an improvement in disease activity; with an improvement in mean (±SD) IMPACT 3 score from 132.1 (±18.8) to 140.9 (±16.9). AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.
Study D9422C00002 was an open-label, un-comparative study designed to evaluate Nalator 6 mg once daily as maintenance treatment in 50 pediatric patients (children and adolescents aged 5 to 17 years) with a diagnosis of mild to moderate Crohn's disease of the ileum and/or ascending colon who were in clinical remission (PCDAI ≤10). Treatment consisted of a 12-week maintenance treatment phase of 6 mg once daily, a 2-week taper phase to 3 mg once daily. The median duration of treatment exposure of Nalator was 98.5 days (range: 11 days to 135 days). Most patients remained in the clinical remission stage, as there were no major changes in the mean PCDAI composite score or IMPACT 3 score. Mean (SD) PCDAI was 4.85 (3.62) at baseline and 6.89 (8.08) after 12 weeks of maintenance treatment with Nalator 6 mg daily. At the same points in time the mean IMPACT3 score was 145.62 (12.43) and 146.98 (15.48), respectively. AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.
Absorption
In adults the systemic availability of Nalator following administration of Nalator Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
Distribution
Nalator has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.
Biotransformation
Nalator undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxyNalator and 16α-hydroxyprednisolone, is less than 1 % of that of Nalator. The metabolism of Nalator is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination
The metabolites of Nalator are excreted as such or in conjugated form mainly via the kidneys. No unchanged Nalator has been detected in the urine. Nalator has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of Nalator after iv dosing averages 2-3 hours.
Linearity
The kinetics of Nalator are dose-proportional at clinically relevant doses.
Paediatric population
Nalator has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of Nalator after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of Nalator following administration of Nalator Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of Nalator following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
Absorption
After oral application the systemic availability of budesonide is about 10 %. After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2 - 3 hours after administering Nalator 2mg rectal foam.
Distribution
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85 - 90 %.
Biotransformation
Budesonide undergoes extensive biotransformation in the liver (approximately 90 %) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 β - hydroxybudesonide and 16 α - hydroxyprednisolone, is less than 1 % of that of budesonide.
Elimination
The average elimination half-life is about 3 - 4 hours. The mean clearance rate is about 10 - 15 L/min for budesonide, determined by HPLC-based methods.
Spread
A scintigraphic investigation with technetium-marked Nalator 2mg rectal foam on patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.
Specific patient populations (liver diseases)
Dependent on the type and severity of liver diseases the metabolism of budesonide might be decreased.
Absorption
In adults the systemic availability of budesonide following administration of Nalator Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
Distribution
Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.
Biotransformation
Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination
The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2 - 3 hours.
Linearity
The kinetics of budesonide are dose-proportional at clinically relevant doses.
In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.
Paediatric population
Budesonide has a systemic clearance of approximately 0.5 L/min in 4 - 6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4 - 6 years old asthmatic children, the systemic availability of budesonide following administration of Nalator Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults.
The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4 - 6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4 - 6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
Absorption
Following oral inhalation via Nalator, peak plasma concentrations of budesonide (4.0 nmol/L after a dose of 800 μg) occur within 30 minutes. Maximum plasma concentration and area under the plasma concentration time profile increase linearly with dose, but are slightly (20-30%) higher following repeated doses (3 weeks treatment) than after a single dose. Lung deposition in healthy subjects was estimated to 34% ±10% of the metered dose (arithmetic mean ± SD), while 22% was retained in the mouthpiece and the rest (approximately 45% of the metered dose) was swallowed.
The maximal plasma concentration after inhalation of 1 milligram budesonide is about 3.5 nmol/L and is reached after about 20 minutes.
Distribution
Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.
Biotransformation
Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome p450.
Excretion
The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2-3 hours.
Linearity
The kinetics of budesonide are dose-proportional at clinically relevant doses.
In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.
Paediatric safety data
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In asthmatic children treated with Nalator (800 μg single dose), plasma concentration reached Cmax (4.85 nmol/L) at 13.8 minutes after inhalation, and then decreased rapidly; AUC was 10.3 nmol·h/L. The value for AUC is generally comparable to that observed in adults at the same dose, however, the Cmax value tends to be higher in children. Lung deposition in children (31% of the nominal dose) is similar to that measured in healthy adults (34% of nominal dose).
Absorption
After oral dosing of plain micronised compound, absorption seems to be complete. A large proportion of the unformulated drug is absorbed from the ileum and ascending colon.
Systemic availability of Budesonide following a single administration of Nalator tablets in healthy volunteers was compared to that of Entocort and the result was similar, about 10%, due to first pass metabolism in the liver. Maximum plasma concentrations of budesonide are approximately 1.3-1.8 ng/ml at 13-14 hours post administration. Concomitant administration of Nalator tablets with food had no clinically relevant effect on absorption. It has been shown that there is no potential for drug accumulation on repeated dosing.
Distribution
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85-90%.
Biotransformation
Budesonide undergoes extensive biotransformation in the liver to metabolites of low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination
Elimination of budesonide is rate limited by absorption. Budesonide has a high systemic clearance (about 1.2 L/min).
Paediatric Population
No data or experience is available with respect to the pharmacokinetics of Nalator tablets in the paediatric population.
Bioavailablity of oral budesonide in man is low (11-13%) due to an extensive first-pass metabolism in the liver.
The systemic availability of budesonide from this medicine, with reference to the metered dose is 33%. In adults, the maximal plasma concentration after administration of 256 micrograms budesonide from this medicine is 0.64 nM and is reached within 0.7 hours. The AUC after administration of 256 micrograms budesonide from this medicine is 2.7 nmolxh/L in adults.
Absorption
After oral dosing of plain micronised compound, absorption is rapid and seems to be complete. A large proportion of the drug is absorbed from the ileum and ascending colon. Systemic availability in healthy subjects is approximately 9-12% for Nalator CR Capsules. This is similar to the systemic availability of plain micronised budesonide, indicating complete absorption. In patients with active Crohn's disease systemic availability is approximately 12-20% at the start of treatment.
Distribution
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85-90%. In healthy volunteers mean maximal plasma concentrations of 5-10 nmol/L were seen at 3-5 hours following a single oral dose of Nalator CR Capsules 9 mg.
Biotransformation
Budesonide then undergoes extensive biotransformation in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination
Elimination is rate limited by absorption. The average terminal half-life is 4 hours. Budesonide has a high systemic clearance (about 1.2 L/min).
Paediatric population
In a study comparing the pharmacokinetics of Nalator CR Capsules in 8 children (range 9-14 years) and 6 adults, Nalator CR Capules 9 mg for 7 days induced a systemic exposure (AUC) that was 17% higher in children than in adults, with maximum concentrations (Cmax) 50% higher in children than in adults (mean AUC ± SD: children 41.3 nmol/L ± 21.2; adults 35.0 nmol/L ± 19.8. Mean Cmax ± SD: children 5.99 nmo/L ± 3.45; adults 3.97 nmo/L ± 2.11.) (Study 08-3044).
Side effects typical of systemic corticosteroids may occur. Potential systemic effects include glaucoma.
Visual disturbance
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.
Use 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 glucocorticosteroids may have unwanted effects.
Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.
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.
Treatment with Nalator CR Capsules results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. When patients are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Nalator CR Capsules, they may have adrenocortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients and their dose of systemic steroid should be reduced cautiously.
Replacement of high systemic effect glucocorticosteroid treatment with Nalator CR Capsules, sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.
Chicken pox and measles can have a more serious course in patients on oral glucocorticosteroids. 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 glucocortiocosteriods treatment and immediately consult a physician. Glucocorticosteroids may cause suppression of the hypothalamus-pituitary-adrenal (HPA) axis and reduce the stress response. Where patients are subject to surgery or other stress situations, supplementary systemic glucocorticoid treatment is recommended.
Reduced liver function may affect the elimination of glucocorticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. The pharmacokinetics after oral ingestion of budesonide was affected by compromised liver function as evidenced by increased systemic availability in patients with moderately severe hepatic cirrhosis.
When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy. Some patients feel unwell in a non-specific way during the withdrawal phase, e.g. pain in muscles and joints. A general insufficient glucocorticosteroid 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 glucocorticosteroids is sometimes necessary.
Co-treatment with CYP3A inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side-effects.).
After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times.
When Nalator CR Capsules are used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.
Paediatric population
It is recommended that the height of children receiving prolonged treatment with glucocorticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated. The benefits of the glucocorticosteroid therapy and the possible risks of growth suppression must be carefully weighed. Long-term studies have not been performed in children treated with Nalator CR Capsules.
Inhaled Nalator has no or negligible influence on the ability to drive and use machines.
No studies on the effects on the ability to drive and use machines have been performed.
Nalator Respules has no or negligible influence on the ability to drive and use machines.
Nalator has no or negligible influence on the ability to drive and use machines.
No studies on the effects of Nalator 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.
This medicine has no or negligible influence on the ability to drive and use machines.
Nalator CR Capsules have no or negligible influence on the ability to drive and use machines.
Posology
Adults
Active Crohn's disease: The recommended daily dose for induction of remission is 9 mg once daily in the morning, for up to eight weeks. The full effect is usually achieved within 2-4 weeks.
When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy.
Active Microscopic colitis: The recommended dose is 9 mg once daily in the morning (corresponding to 3 capsules).
Paediatric population
There are limited data on the use of Nalator CR Capsules in children. The available data are insufficient to support safety and efficacy in the paediatric population, therefore such use cannot be recommended until further data become available.
Older people
No special dose adjustment is recommended. However, experience with Nalator CR Capsules in older people is limited.
Method of administration
The capsules should be swallowed whole with water. The capsules must not be chewed.
Before using this medicine for the first time the nozzle must be primed (filled with the medicine). To do this the bottle is shaken and the protective cap removed. The bottle is then held upright and the nozzle pumped up and down several times (5-10 times) spraying into the air, until an even mist is seen. The priming effect remains for approximately 24 hours. If a longer period of time passes before the next dose is taken, the nozzle must be loaded with medicine again. This time it is sufficient to spray just once into the air.
a. The patient is then instructed to blow their nose. Next, the bottle needs to be shaken and the protective cap removed.
b. The bottle is then held upright, with one finger held on either side of the nozzle.
c. The tip of the nozzle is inserted into the nostril and the nozzle pressed down once (or more as instructed by the doctor). The spray is then administered into the other nostril in the same way. Note: it is not necessary to inhale at the same time as spraying.
d. The nozzle needs to be wiped with a clean tissue after use and the protective cap replaced. The bottle should be stored in an upright position.
e. Keeping the Nalator nozzle clean
The plastic nozzle of Nalator should be cleaned regularly and at any time the spray of medicine is not coming out as it should. If this happens, first the nozzle should be checked to ensure that it is primed with medicine (see earlier). If, after the nozzle is primed again, the pump is still not working, the nozzle should be cleaned by using the following instructions:
The plastic nozzle is removed with a clean tissue and washed in warm, not hot, water. The nozzle is then rinsed thoroughly, dried and then replaced onto the top of the bottle. The nozzle should not be unblocked with a pin or other sharp object. After cleaning, the nozzle must be primed (filled with medicine) again before use.
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
