1 INDICATIONS AND USAGE PULMICORT RESPULES® is an inhaled corticosteroid indicated for: •Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age (1.1) Important Limitations of Use: Not indicated for the relief of acute bronchospasm (1.1) 1.1 Maintenance Treatment of Asthma PULMICORT RESPULES is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age. Important Limitations of Use: •PULMICORT RESPULES is NOT indicated for the relief of acute bronchospasm.
| Previous Therapy || Recommended Starting Dose || Highest Recommended Dose |
| Bronchodilators alone || 0.5 mg total daily dose administered either once daily or twice daily in divided doses || 0.5 mg total daily dose |
| Inhaled Corticosteroids || 0.5 mg total daily dose administered either once daily or twice daily in divided doses || 1 mg total daily dose |
| Oral Corticosteroids || 1 mg total daily dose administered either as 0.5 mg twice daily or 1 mg once daily || 1 mg total daily dose |
3 DOSAGE FORMS AND STRENGTHS PULMICORT RESPULES is available in three strengths, each containing 2 mL: 0.25 mg/2 mL, 0.5 mg/2mL, and 1 mg/2 mL. PULMICORT RESPULES is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose RESPULES ampules together with patient instructions for use. There are 30 RESPULES ampules in a carton. Each single-dose RESPULES ampule contains 2 mL of sterile liquid suspension. Inhalation suspension: 0.25 mg/2mL, 0.5 mg/2mL, 1 mg/2mL (3)
4 CONTRAINDICATIONS The use of PULMICORT RESPULES is contraindicated in the following conditions: •Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. •Hypersensitivity to budesonide or any of the ingredients of PULMICORT RESPULES [see Warnings and Precautions (5.3), Description (11) and Adverse Reactions, Post-marketing Experience (6.2) ]. •Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. (4.1) •Hypersensitivity to any of the ingredients in PULMICORT RESPULES (4.2)
5 WARNINGS AND PRECAUTIONS •Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.1) •Deterioration of disease and acute asthma episodes: Do not use for the relief of acute bronchospasm. (5.2) •Hypersensitivity reactions: anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur (5.3) •Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.4) •Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to PULMICORT RESPULES. (5.5) •Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, reduce PULMICORT RESPULES slowly. (5.6) •Reduction in bone mineral density with long term administration. Monitor patients with major risk factors for decreased bone mineral content. (5.7) •Effects on growth: Monitor growth of pediatric patients. (5.8) •Glaucoma and cataracts: Close monitoring is warranted. (5.9) •Paradoxical bronchospasm: Discontinue PULMICORT RESPULES and institute alternative therapy if paradoxical bronchospasm occurs. (5.10) •Eosinophilic conditions and Churg-Strauss syndrome: Be alert to eosinophilic conditions. (5.11) 5.1 Local Effects In clinical trials with PULMICORT RESPULES, 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 PULMICORT RESPULES treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with PULMICORT RESPULES. Patients should rinse the mouth after inhalation of PULMICORT RESPULES. 5.2 Deterioration of Disease and Acute Asthma Episodes PULMICORT RESPULES 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 PULMICORT RESPULES. During such episodes, patients may require therapy with oral corticosteroids. 5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see Contraindications (4) ]. 5.4 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 package inserts for 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 PULMICORT RESPULES. 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 PULMICORT RESPULES 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (i.e., beta2-agonists, 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 PULMICORT RESPULES (85%) compared to patients treated with non-corticosteroid asthma therapy (90%). No patient treated with PULMICORT RESPULES 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. 5.5 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 PULMICORT RESPULES 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 PULMICORT RESPULES. Initially, PULMICORT RESPULES 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 PULMICORT RESPULES may unmask allergic or other immunologic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eosinophilic conditions, eczema, and arthritis [see Dosage and Administration (2) ]. 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. 5.6 Hypercorticism and Adrenal Suppression PULMICORT RESPULES, 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 PULMICORT RESPULES. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT RESPULES should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients post-operatively 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 budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of PULMICORT RESPULES should be reduced slowly, consistent with accepted procedures for tapering of systemic corticosteroids and for management of asthma. 5.7 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. 5.8 Effects on Growth Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving PULMICORT RESPULES routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see Use In Specific Populations, Pediatric Use (8.4) ]. 5.9 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. 5.10 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 PULMICORT RESPULES, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with PULMICORT RESPULES should be discontinued and alternate therapy instituted. 5.11 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 budesonide and these underlying conditions has not been established. 5.12 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of PULMICORT RESPULES 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 Drug Interactions (7.1)and Clinical Pharmacology, Clinical Pharmacokinetics (12.3) ].
6 ADVERSE REACTIONS Systemic and inhaled corticosteroid use may result in the following: • Candida albicans infection [see Warnings and Precautions (5.1) ] •Hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.3) ] •Immunosuppression [see Warnings and Precautions (5.4) ] •Hypercorticism and adrenal suppression [see Warnings and Precautions (5.6) ] •Reduction in bone mineral density [see Warnings and Precautions (5.7) ] •Growth effects in pediatric patients [see Warnings and Precautions (5.8)and Use in Specific Populations, Pediatric Use (8.4) ] •Glaucoma, increased intraocular pressure and cataracts [see Warnings and Precautions (5.9) ] •Eosinophilic conditions and Churg-Strauss syndrome [see Warnings and Precautions (5.11) ] Adverse reactions at an incidence of >3%: Respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1–800–236–9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions is based on three double-blind, placebo-controlled, randomized U.S. clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients ≥12 months and <2 years of age; 225 patients ≥2 and <4 years of age; and 622 patients ≥4 and ≤8 years of age) were treated with PULMICORT RESPULES (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for PULMICORT RESPULES was comparable to that reported for placebo. The following table shows the incidence of adverse events in U.S. controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators and/or inhaled corticosteroids. This population included a total of 605 male and 340 female patients and 78.4% were Caucasian, 13.8% African American, 5.5% Hispanic and 2.3% Other. Table 1 – Adverse Reactions occurring at an incidence of ≥3% in at least one active treatment group where the incidence was higher with PULMICORT RESPULES than placebo Adverse Events Vehicle Placebo (n=227) % PULMICORT RESPULES Total Daily Dose 0.25 mg (n=178) % 0.5 mg (n=223) % 1 mg (n=317) % Respiratory System Disorder Respiratory Infection 36 34 35 38 Rhinitis 9 7 11 12 Coughing 5 5 9 8 Resistance Mechanism Disorders Otitis Media 11 12 11 9 Viral Infection 3 4 5 3 Moniliasis 2 4 3 4 Gastrointestinal System Disorders Gastroenteritis 4 5 5 5 Vomiting 3 2 4 4 Diarrhea 2 4 4 2 Abdominal Pain 2 3 2 3 Hearing and Vestibular Disorders Ear Infection 4 2 4 5 Platelet, Bleeding and Clotting Disorders Epistaxis 1 2 4 3 Vision Disorders Conjunctivitis 2 <1 4 2 Skin and Appendages Disorders Rash 3 <1 4 2 The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one PULMICORT RESPULES treatment group where the incidence was higher with PULMICORT RESPULES than with placebo, regardless of relationship to treatment. Blood and lymphatic system disorders: cervical lymphadenopathy Ear and labyrinth disorders: earache General disorders and administration site conditions: fatigue, flu-like disorder Immune system disorders: allergic reaction Infections and infestations: eye infection, herpes simplex, external ear infection, infection Injury, poisoning and procedural complication: fracture Metabolism and nutrition disorders: anorexia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: hyperkinesia Psychiatric disorders: emotional lability Respiratory, thoracic, and mediastinal disorders: chest pain, dysphonia, stridor Skin and subcutaneous tissue disorders: contact dermatitis, eczema, pustular rash, pruritus, purpura The incidence of reported adverse events was similar between the 447 PULMICORT RESPULES-treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies. 6.2 Post-marketing Experience The following adverse reactions have been reported during post-approval use of PULMICORT RESPULES. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with PULMICORT RESPULES. Endocrine disorders: symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.5) ] Eye disorders: cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)] General disorders and administration site conditions: fever, pain Immune system disorders: immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria [see Contraindications (4)and Warnings and Precautions (5.10)] Infection and Infestation: sinusitis, pharyngitis, bronchitis Musculoskeletal and connective tissue disorders: avascular necrosis of the femoral head, osteoporosis, growth suppression Nervous system disorders: headache Psychiatric disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety Respiratory, thoracic, and mediastinal disorders: cough, dysphonia and throat irritation Skin and subcutaneous tissue disorders: skin bruising, facial skin irritation Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for PULMICORT RESPULES [see Warnings and Precautions (5.8)and Use In Specific Populations, Pediatric Use (8.4) ].
7 DRUG INTERACTIONS •Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (5.12, 7.1) 7.1 Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of PULMICORT RESPULES with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.12)and Clinical Pharmacology, Pharmacokinetics (12.3) ].
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category B – Studies of pregnant women, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (ie, Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively). These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%). Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT RESPULES should be used during pregnancy only if clearly needed. As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis and at subcutaneous dose that was approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis. In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. Non-teratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed. 8.3 Nursing Mothers Budesonide, like other corticosteroids, is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology, Pharmacokinetics (12.3),and Use In Specific Populations, Nursing Mothers (8.3) ]. No studies have been conducted in breastfeeding women with PULMICORT RESPULES; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. PULMICORT RESPULES should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant. 8.4 Pediatric Use Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see Clinical Pharmacology, Pharmacodynamics (12.2), and Adverse Reactions, Clinical Trials Experience (6.1) ]. A 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 PULMICORT RESPULES or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received PULMICORT RESPULES versus placebo. However, on an individual basis, 7 patients in this study (6 in the PULMICORT RESPULES treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see Clinical Pharmacology, Pharmacodynamics (12.2) ]. Pneumonia was observed more frequently in patients treated with PULMICORT RESPULES than in patients treated with placebo, (N = 2, 1, and 0) in the PULMICORT RESPULES 0.5 mg, 1 mg, and placebo groups, respectively. A dose dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the PULMICORT RESPULES 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and PULMICORT RESPULES 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and PULMICORT RESPULES 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of PULMICORT RESPULES in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. In a study of asthmatic children 5-12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with the budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The growth of pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2)and Warnings and Precautions (5.8) ]. 8.5 Geriatric Use Of the 215 patients in 3 clinical trials of PULMICORT RESPULES in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients. 8.6 Hepatic Impairment Formal pharmacokinetic studies using PULMICORT RESPULES have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.