PULMIREMA nebuliser suspension is indicated for the maintenance treatment of asthma
and as prophylactic therapy in children 12 months to 8 years of age.

Limitations of use
PULMIREMA nebuliser suspension is not indicated for the relief of acute
bronchospasm.
 

Posology

The recommended starting dose and highest recommended dose of PULMIREMA, based on prior asthma therapy, are listed in the following table.

Dosing recommendations based on previous therapy are as follows:

•         Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily

•         Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily

•         Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily

In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.

Method of administration

For inhalation use only.

PULMIREMA  respules  should  be   administered   via  jet   nebulizer   connected   to an air compressor with an  adequate  air  flow,  equipped  with  a  mouthpiece  or suitable face mask. Ultrasonic nebulizers are not suitable for  the  adequate administration of PULMIREMA respules and, therefore, are NOT recommended.

The effects of mixing PULMIREMA respules  with  other  nebulizable  medications have not been adequately assessed. PULMIREMA respules should be administered separately in the nebulizer (see Patient information leaflet)

Local effects

In clinical trials with PULMIREMA, localized infections with Candida albicans occurred in the mouth and pharynx in some patients. The incidences of localized  infections  of Candida albicans were similar between the placebo and PULMIREMA treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with PULMIREMA. Patients should rinse the mouth after inhalation of PULMIREMA.

Deterioration of disease and acute asthma episodes

PULMIREMA is not a bronchodilator and is not indicated for the rapid relief of acute bronchospasm or other acute episodes of asthma.

Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with PULMIREMA. During such episodes, patients may require therapy with oral corticosteroids.

Hypersensitivity reactions including anaphylaxis

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of  PULMIREMA. Discontinue PULMIREMA if such reactions occur.

Immunosuppression

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective ssummary of product characteristicsf or complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered.

The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied. However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with PULMIREMA. An open- label non-randomized clinical study examined the immune responsiveness of varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with PULMIREMA 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., beta2agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥5.0 (gpELISA value) in response to the vaccination was similar in patients treated with PULMIREMA (85%) compared to patients treated with non- corticosteroid asthma therapy (90%). No patient treated with PULMIREMA developed chicken pox as a result of vaccination.

Inhaled corticosteroids should be used with caution, if at all, in patients with active or

quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Transferring patients from systemic corticosteroid therapy

Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary- adrenal (HPA)-axis function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although PULMIREMA may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instructions. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMIREMA. Initially, PULMIREMA should be used concurrently with the  patient’s  usual  maintenance  dose  of  systemic  corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid may be initiated by reducing the daily or alternate daily dose. Further incremental reductions may be made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 25% of the prednisone dose or its equivalent. A slow rate of withdrawal is strongly recommended.

Lung function (FEV1 or AM PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to PULMIREMA may unmask allergic or other immunologic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eosinophilic conditions, eczema, and arthritis.

During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

Hypercorticism and adrenal suppression

PULMIREMA, will often help control asthma symptoms with less suppression of HPA function

than therapeutically equivalent oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing

PULMIREMA. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMIREMA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.  It  is   possible   that   systemic   corticosteroid   effects   such   as hypercorticism,   and   adrenal   suppression (including adrenal crisis) may appear in a small number  of  patients,  particularly  when PULMIREMA is administered at higher than recommended doses over prolonged periods of time.  If  such  effects occur, the dosage of PULMIREMA should be reduced slowly, consistent with accepted procedures for tapering of systemic corticosteroids and for management of asthma.

Reduction in bone mineral density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for  decreased  bone  mineral  content,  such  as  prolonged  immobilization,   family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass  (e.g.,  anticonvulsants  and  corticosteroids),  should  be  monitored  and   treated with established standards of care.

Effects on growth

Orally inhaled corticosteroids, including PULMIREMA, may cause  a  reduction  in growth velocity when administered to pediatric  patients.  Monitor  the  growth  of pediatric patients receiving PULMIREMA  routinely  (e.g.,  via  stadiometry).  To minimize the systemic effects of orally inhaled corticosteroids, including budesonide respules, each patient should be titrated to his/her lowest effective dose (see section 5.1).

Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision  or  with  a  history  of increased intraocular pressure, glaucoma, and/or cataracts.

Paradoxical bronchospasm and upper airway symptoms

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If acute bronchospasm occurs following dosing with   PULMIREMA,   it   should   be   treated   immediately   with    a    fast-acting inhaled bronchodilator. Treatment with PULMIREMA should be discontinued and alternate therapy instituted.

Eosinophilic conditions and Churg-Strauss Syndrome

In rare cases, patients on  inhaled  corticosteroids  may  present  with  systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg- Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually,  but  not  always,  have  been  associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship  between PULMIREMA and these underlying conditions has not been established.

Drug interactions with strong Cytochrome P450 3A4 inhibitors

Caution should be exercised when considering the coadministration of budesonide with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur (see sections 4.5 and 5.2).

The metabolism of PULMIREMA is primarily mediated by CYP3A4. Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat- containing products, are expected to increase the risk of systemic side effects (see Section 4.4 and Section 5.2).

The combination of PULMIREMA with potent CYP3A inhibitors 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 PULMIREMA is co- administered with anti-fungals (such as itraconazole and ketoconazole), the period between treatments should be as long as possible. A reduction of the PULMIREMA dose could be considered.

Limited data about this interaction for high-dose inhaled PULMIREMA indicate that marked increases in plasma levels (on average four-fold) may occur if itraconazole, 200 mg once daily, is administered concomitantly with inhaled PULMIREMA (single dose of 1000 µg).

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

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

Paediatric population

Interaction studies have only been performed in adults

  Pregnancy

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 PULMIREMA during pregnancy.

In animal studies, glucocorticosteroids have been shown to induce malformations (see section 5.3). This is not likely to be relevant for humans given recommended doses, but therapy with inhaled PULMIREMA should be regularly reviewed and maintained at the lowest effective dose. 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 PULMIREMA for the mother should be weighed against the risks to the foetus.

Inhaled glucocorticosteroids should be considered in preference to oral glucocorticosteroids because of the lower systemic effects at the doses required to achieve similar pulmonary

responses.

Breast-feeding

PULMIREMA is excreted in breast milk. However, at therapeutic doses of PULMIREMA no effects on the suckling child are anticipated. PULMIREMA can be used during breast- feeding.

Maintenance treatment with inhaled PULMIREMA (200 or 400 micrograms twice daily) in asthmatic nursing women results in negligible systemic exposure to PULMIREMA 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. PULMIREMA concentrations in infant plasma samples were all less than the limit of quantification.

Based on data from inhaled PULMIREMA and the fact that PULMIREMA exhibits linear PK properties within the therapeutic dosage intervals after nasal, inhaled, oral and rectal administrations, at therapeutic doses of PULMIREMA, exposure to the breast-fed child is anticipated to be low.

PULMIREMA respules has no or negligible  influence  on  the  ability to  drive and use machines

The following definitions apply to the incidence of undesirable effects: 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).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

* refer to Description of selected adverse reactions; facial skin irritation below

** refer to Paediatric population, below

*** based on frequency reported in clinical trials

**** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity (see section 4.4).

Description of selected adverse reactions

The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases (see Section 4.4).

Facial skin irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation, the facial skin should be washed with water after use of the face mask.

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

As per the reference, Clinical trials with 13119 patients on inhaled PULMIREMA and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled PULMIREMA and 0.63% on placebo; that of depression was 0.67% on inhaled PULMIREMA and 1.15% on placebo.

Paediatric population

Due to the risk of growth retardation in the paediatric population, growth should be monitored as described in section 4.4.

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 by submitting complelete form to npc.drug@sfda.gov.sa.

PULMIREMA Respules contains 0.1 mg/ml disodium edetate which has been shown to cause bronchoconstriction at levels above 1.2 mg/ml. Acute overdosage with PULMIREMA Respules, even in excessive doses, is not expected to be a clinical problem.

Mechanism of action

PULMIREMA is an anti-inflammatory corticosteroid that  exhibits  potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, PULMIREMA has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, PULMIREMA is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The clinical significance of these findings is unknown.

The  activity  of  PULMIREMA  respules  is  due   to   the   parent   drug, PULMIREMA. In glucocorticoid receptor affinity studies, the 22R  form  was  two times as active as the 22S epimer. In vitro studies indicated that the two forms of PULMIREMA do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple   cell   types   (e.g.,   mast   cells,   eosinophils,   neutrophils,   macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic-and non-allergic- mediated inflammation. The anti- inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti- inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled  PULMIREMA  in  a  variety  of  formulations  and   delivery   systems including an inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for  nebulization.  This  is  explained  by  a  combination  of  a  relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%) and the low potency of metabolites (see below).

Pharmacodynamics

The therapeutic effects of conventional doses of orally inhaled PULMIREMA are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled PULMIREMA,   a   clinical   study   in   adult   patients    with    asthma    was performed comparing 400 mcg  PULMIREMA  administered  via  a  pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral PULMIREMA  and placebo. The study demonstrated  the  efficacy  of inhaled  PULMIREMA  but  not orally  administered  PULMIREMA,   even   though   systemic   PULMIREMA exposure was comparable  for  both  treatments,  indicating  that  the  inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled PULMIREMA are largely explained by its direct action  on  the respiratory tract.

Improvement in the control of asthma symptoms following inhalation of budesonide respules can occur within 2-8 days of beginning treatment, although maximum benefit may not be achieved for 4-6 weeks.

PULMIREMA administered via a dry powder inhaler has been shown  in  various challenge models (including histamine, methacholine, sodium metabisulfite,  and adenosine monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain.

Pre-treatment with PULMIREMA administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late- phase reaction) decrease in FEV1 following inhaled allergen challenge.

HPA axis effects

The effects of PULMIREMA respules on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with PULMIREMA respules treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMIREMA respules equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141  pediatric  patients  6   to   12   months   of   age with mild to  moderate  asthma  or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMIREMA respules or placebo once daily. A total of 28, 17, and 31 patients in the PULMIREMA respules 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with PULMIREMA respules versus placebo. However, 7 patients in this study (4 of whom received budesonide respules 0.5 mg, 2 of whom received PULMIREMA respules 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (≥500 nmol/L) to a subnormal level (<500 nmol/L) at Week

12. In 4 of these patients receiving PULMIREMA respules, the cortisol values were near the cutoff value of 500 nmol/L.

The effects of PULMIREMA respules at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of PULMIREMA respules (1 and 2 mg twice daily) showed statistically significantly reduced (4352%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of PULMIREMA respules, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.

PULMIREMA respules, like other  inhaled  corticosteroid  products,  may  impact  the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods (see section 4.4).

Clinical studies

Three double-blind, placebo-controlled, parallel group, randomized U.S. clinical trials of 12- weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. Doses of

0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari- LC-Jet  Plus  Nebulizer  (with  a  face  mask  or  mouthpiece)  connected  to  a   Pari Master compressor was used to deliver PULMIREMA respules to patients in the 3 U.S. controlled clinical  trials.  The  co-primary  endpoints  were  nighttime  and  daytime asthma symptom scores (0-3 scale). Improvements were addressed in terms  of  the primary efficacy variables of changes from  baseline  to  the  double-blind  treatment period in nighttime and daytime asthma symptom scores (scale 0-3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization).  The  double-blind treatment period was defined as the mean over 12- week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U.S. studies.

Results of the 3 controlled clinical trials for recommended dosages of PULMIREMA inhalation suspension (0.25 mg to 0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of  1  mg)  in  946  patients,  12  months  to  8  years  of  age,   are presented below.  Statistically  significant  decreases  in  night  time  and  daytime symptom scores of asthma were observed at PULMIREMA respules doses of 0.25  mg once daily (one study), 0.25 mg twice daily, and 0.5 mg  twice  daily  compared  to placebo. Use of PULMIREMA respules resulted in statistically significant decreases in either night time or daytime symptom scores, but not both, at doses of 1 mg once daily, and

0.5 mg once daily (one study). Symptom reduction in  response  to  PULMIREMA respules occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of PULMIREMA respules studied.

Improvements in lung function were associated with PULMIREMA respules in the subgroup of patients capable of  performing  lung  function  testing.  Statistically significant increases were seen in FEV1 [PULMIREMA respules 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [PULMIREMA respules 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo.

A numerical reduction in night time and daytime symptom scores (0-3 scale) of asthma was observed within 2-8 days, although maximum benefit was not achieved for 4-6 weeks after starting treatment. The reduction in night time and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials.

Patients not receiving inhaled corticosteroid therapy

The efficacy of PULMIREMA respules at doses of 0.25 mg, 0.5 mg, and 1 mg once daily was evaluated  in  344   pediatric   patients,   12   months   to   8   years   of   age,   with mild  to  moderate  persistent  asthma  (mean  baseline  night  time  asthma  symptom scores of the treatment groups ranged from 1.07 to 1.34) who were not well controlled by bronchodilators alone. The changes from baseline to Weeks 0-12 in night time asthma symptom scores are shown in Figure 1.

Night time asthma symptom scores   showed   statistically   significant   decreases   in the patients treated with PULMIREMA respules compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

Changes from baseline to the double-blind phase for the PULMIREMA treatment groups compared to placebo were made using analysis of variance techniques. The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables (see Figures 1- 3).

p-value – 0.25 mg: 0.001, 0.5 mg: 0.010, 1.0 mg: 0.009

Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline

Patients previously maintained on inhaled corticosteroids

The efficacy of PULMIREMA respules at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4   to   8   years   of   age,   previously maintained on inhaled corticosteroids (mean FEV1 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between

42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day). The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decrease in patients treated with PULMIREMA respules compared to placebo. Similar decreases were also   observed   for   daytime asthma symptom scores.

Statistically significant increases in FEV1 compared to placebo were observed with PULMIREMA respules at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily).

p-values: 0.25 mg: 0.022, 0.5 mg: 0.021

Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from                                                                                                       Baseline

Patients receiving once-daily or twice-daily dosing

The efficacy of budesonide respules at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from

1.13 to 1.31). Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure

3. budesonide respules at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

PULMIREMA respules at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV1, and at doses of 0.25 mg and 0.5 mg twice daily and   1 mg once daily statistically significant increases in morning PEF.

The evidence supports the efficacy of the same nominal dose of PULMIREMA respules administered on either a once-daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice-daily dosing (see section 4.2)

p-values: 0.25 mg qd: 0.121, 0.25 mg bid: <0.001, 0.5 mg bid: 0.003, 1.0 mg qd: 0.005

Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline

Absorption

In asthmatic children 4-6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of PULMIREMA respules via jet nebulizer was approximately 6% of the labeled dose.

In children, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization of a 1 mg dose. Systemic exposure, as measured by AUC and Cmax, is similar for young children and adults after inhalation of the same dose of PULMIREMA respules.

Distribution

In asthmatic children 4-6 years of age, the volume of distribution at steady-state of PULMIREMA was 3 L/kg, approximately the  same  as  in  healthy  adults. PULMIREMA is 85-90% bound to plasma proteins, the degree  of  binding  being constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses. PULMIREMA showed little or no binding to corticosteroid-binding globulin. PULMIREMA rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that PULMIREMA is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns has been  detected. Negligible metabolic inactivation was observed in human lung and serum preparations.

Elimination

PULMIREMA is primarily cleared by the liver. PULMIREMA is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged PULMIREMA was detected in the urine.

In asthmatic children 4-6 years of age, the terminal half-life of PULMIREMA after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min,  which  is approximately 50% greater than in healthy adults after adjustment for differences in weight.

Special populations

No differences in pharmacokinetics due to race, gender, or age have been identified.

Hepatic impairment

Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by  compromised  liver  function  as  evidenced  by  a doubled systemic availability  after  oral  ingestion.  The  intravenous  pharmacokinetics of PULMIREMA were, however, similar in cirrhotic patients and in healthy adults.

Preclinical data revealed no special hazard for humans in the therapeutic dose range based on studies of chronic toxicity, genotoxicity and carcinogenicity.

Glucocorticoids, including PULMIREMA, 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.

excipients

Polysorbate 80, Sodium chloride, Edetate disodium,

Sodium citrate,

Citric acid monohydrate, Water for injection.

Nitrogen

Not applicable.

Do not store above 30°C, Protect from light, Do not freeze After opening Do not store above 30°C, Dont Freeze.

Store the Respules in the foil envelope to protect them from light. Units should be stored in an upright position and should be protected from freezing.

Carton containing 6 combi pack having 5 respules of 2 ml each.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.