Pulmicort Respules

Description

Budesonide, the active ingredient in PULMICORT RESPULES®, is a corticosteroid with the chemical designation of (RS)-11β, 16α, 17, 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, 17-acetal with butyraldehyde. It is supplied as a mixture of two epimers, specifically the 22R and 22S forms. The empirical formula for budesonide is C25H34O6, and it has a molecular weight of 430.5 g/mol.

Budesonide appears as a white to off-white, tasteless, and odorless powder. It is characterized by its low solubility profile, being practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. The partition coefficient between octanol and water at pH 7.4 is 1.6 x 10^3.

PULMICORT RESPULES is formulated as a sterile suspension intended for inhalation via jet nebulizer. Each ampule contains micronized budesonide along with inactive ingredients, including disodium edetate, sodium chloride, sodium citrate, citric acid, polysorbate 80, and Water for Injection. The product is available in three dose strengths: 0.25 mg, 0.5 mg, and 1 mg per 2 mL ampule.

The delivery of budesonide to the lungs during nebulization is influenced by various patient factors, the specific jet nebulizer used, and the performance of the compressor. In in vitro studies using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, the mean delivered dose at the mouthpiece was approximately 17% of the nominal dose at a mean flow rate of 5.5 L/min, with a mean nebulization time of 5 minutes or less. PULMICORT RESPULES should be administered using jet nebulizers at appropriate flow rates, utilizing either face masks or mouthpieces.

Uses and Indications

Pulmicort Respules® is indicated for the maintenance treatment of asthma and as prophylactic therapy in pediatric patients aged 12 months to 8 years.

This drug is not indicated for the relief of acute bronchospasm. There are no teratogenic or nonteratogenic effects associated with its use.

Dosage and Administration

The initial dosing regimen should commence with the lowest recommended dose tailored to the specific treatment modality. For bronchodilators administered alone, the recommended starting dose is 0.5 mg once daily or 0.25 mg twice daily. In the case of inhaled corticosteroids, the starting dose is similarly 0.5 mg once daily or 0.25 mg twice daily, with the option to increase to a maximum of 0.5 mg twice daily if necessary. For oral corticosteroids, the initial dosing can be set at 0.5 mg twice daily or 1 mg once daily.

In symptomatic children who do not respond adequately to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. Should once-daily treatment fail to achieve sufficient control of symptoms, it is recommended to increase the total daily dose and/or to administer the dose in divided intervals. Once asthma stability is attained, a gradual titration downwards of the dose is advised.

This medication is intended for inhalation use exclusively via compressed air-driven jet nebulizers; it is not suitable for use with ultrasonic devices and is not for injection.

Contraindications

Use of PULMICORT RESPULES is contraindicated in the following situations:

Patients requiring primary treatment for status asthmaticus or other acute episodes of asthma that necessitate intensive measures. This is due to the need for immediate and aggressive intervention in such cases.

Additionally, PULMICORT RESPULES should not be used in individuals with a known hypersensitivity to any of its ingredients, as this may lead to severe allergic reactions.

Warnings and Precautions

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur in patients using PULMICORT RESPULES. It is essential to monitor patients periodically for signs of adverse effects on the oral cavity. Patients should be advised to rinse their mouths following inhalation to mitigate this risk.

PULMICORT RESPULES is not indicated for the relief of acute bronchospasm. Therefore, healthcare professionals should refrain from using this medication in the management of acute asthma episodes, as it may lead to deterioration of the disease.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported in association with PULMICORT RESPULES. Should any of these reactions occur, the medication must be discontinued immediately.

Immunosuppression is a potential concern, particularly in patients with existing infections such as tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is advised when prescribing PULMICORT RESPULES to these patients, as they may experience a more severe or even fatal course of chickenpox or measles.

When transferring patients from systemic corticosteroid therapy to PULMICORT RESPULES, there is a risk of impaired adrenal function. It is recommended to taper patients slowly from oral steroids to minimize this risk.

Hypercorticism and adrenal suppression may occur, particularly with very high dosages or in susceptible individuals. If such changes are observed, it is advised to reduce the dosage of PULMICORT RESPULES gradually.

Long-term administration of PULMICORT RESPULES may lead to a reduction in bone mineral density. Therefore, it is crucial to monitor patients who have major risk factors for decreased bone mineral content.

In pediatric patients, growth should be closely monitored during treatment with PULMICORT RESPULES to ensure that any potential effects on growth are identified and managed appropriately.

Patients should also be monitored for the development of glaucoma and cataracts, as close observation is warranted in these cases.

Paradoxical bronchospasm may occur in some patients. If this reaction is observed, PULMICORT RESPULES should be discontinued, and alternative therapy should be initiated.

Healthcare professionals should remain vigilant for eosinophilic conditions, including Churg-Strauss syndrome, in patients receiving PULMICORT RESPULES.

To ensure patient safety, it is recommended to monitor patients with major risk factors for decreased bone mineral content, track the growth of pediatric patients, and conduct close monitoring for glaucoma and cataracts throughout the course of treatment.

Side Effects

Patients using PULMICORT RESPULES may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Most common adverse reactions include respiratory infections, rhinitis, coughing, otitis media, viral infections, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infections, epistaxis, conjunctivitis, and rash. These reactions were observed in clinical trials and postmarketing experiences.

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur. It is recommended that patients be monitored periodically for signs of adverse effects on the oral cavity, and they should be advised to rinse their mouths following inhalation.

Serious adverse reactions include hypersensitivity reactions such as anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm. If any of these reactions occur, PULMICORT RESPULES should be discontinued immediately. Additionally, there is a risk of immunosuppression, which may lead to the worsening of existing infections, including tuberculosis and ocular herpes simplex. Caution is advised when using this medication in patients with such infections, as a more serious or even fatal course of chickenpox or measles can occur in susceptible individuals.

Patients transitioning from systemic corticosteroid therapy may experience impaired adrenal function. It is crucial to taper patients slowly from oral steroids when transferring to PULMICORT RESPULES. Hypercorticism and adrenal suppression may occur, particularly with very high dosages or in susceptible individuals; if such changes are observed, the dosage of PULMICORT RESPULES should be reduced gradually.

Long-term administration of PULMICORT RESPULES may lead to a reduction in bone mineral density, necessitating monitoring in patients with major risk factors for decreased bone mineral content. Furthermore, the growth of pediatric patients should be closely monitored, as controlled clinical studies have indicated that inhaled corticosteroids may cause a reduction in growth velocity, with a mean reduction of approximately one centimeter per year. The long-term implications of this reduction remain unknown.

Patients should also be monitored for the development of glaucoma and cataracts. In clinical trials, pneumonia was observed more frequently in patients treated with PULMICORT RESPULES compared to those receiving placebo. A dose-dependent effect on growth was noted, with infants in the placebo arm experiencing an average growth of 3.7 cm over 12 weeks, compared to 3.5 cm and 3.1 cm in the PULMICORT RESPULES 0.5 mg and 1 mg arms, respectively.

Paradoxical bronchospasm has been reported; if this occurs, PULMICORT RESPULES should be discontinued, and alternative therapy should be initiated. Additionally, clinicians should remain vigilant for eosinophilic conditions, including Churg-Strauss syndrome, in patients receiving this treatment.

Drug Interactions

The concomitant use of strong Cytochrome P450 3A4 inhibitors, such as ritonavir, should be approached with caution. This combination may lead to an increase in systemic corticosteroid effects, which could heighten the risk of adverse reactions associated with corticosteroid therapy.

Monitoring for signs of increased corticosteroid effects is recommended when these agents are used together. No specific dosage adjustments are provided; however, clinicians should consider the potential for enhanced effects and adjust treatment accordingly based on the patient's clinical response.

Packaging & NDC

The table below lists all NDC Code configurations of Pulmicort Respules (budesonide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Safety and effectiveness of PULMICORT RESPULES in pediatric patients aged six months to 12 months have been evaluated but not established. In children aged 12 months to 8 years, safety and effectiveness have been established. A 12-week study involving 141 pediatric patients aged 6 to 12 months with mild to moderate asthma or recurrent/persistent wheezing assessed the effects of PULMICORT RESPULES at doses of 0.5 mg and 1 mg compared to placebo, administered once daily.

Adrenal-axis function was evaluated using an ACTH stimulation test at the study's start and conclusion, revealing no significant adrenal suppression in the PULMICORT RESPULES group compared to placebo. However, individual assessments indicated that 7 patients (6 in the treatment arms and 1 in the placebo arm) experienced a decline from normal to subnormal stimulated cortisol levels by Week 12. Additionally, pneumonia occurred more frequently in patients receiving PULMICORT RESPULES, with 2 cases in the 0.5 mg group, 1 in the 1 mg group, and none in the placebo group.

The study also noted a dose-dependent effect on growth. Infants in the placebo arm had an average growth of 3.7 cm over 12 weeks, while those in the PULMICORT RESPULES 0.5 mg and 1 mg arms grew 3.5 cm and 3.1 cm, respectively. These findings suggest that PULMICORT RESPULES may lead to systemic effects, including growth suppression, consistent with other studies on inhaled corticosteroids. Controlled clinical studies indicate that inhaled corticosteroids can reduce growth velocity in pediatric patients, with an average reduction of approximately one centimeter per year, influenced by dose and duration of treatment. The long-term implications of this growth reduction on final adult height remain unknown, and the potential for "catch up" growth after discontinuation of treatment has not been adequately studied.

In a separate study of asthmatic children aged 5 to 12 years, those treated with budesonide via a dry powder inhaler at a dose of 200 mcg twice daily experienced a 1.1-centimeter reduction in growth compared to placebo at one year. Therefore, routine monitoring of growth in pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES, is recommended. To minimize systemic effects, each patient should be titrated to the lowest effective dose.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, comprised 30% of the 215 patients enrolled in three clinical trials of PULMICORT RESPULES. Among these, 10% were aged 75 years and older.

Clinical findings indicate that no overall differences in safety were observed between elderly patients and their younger counterparts. Additionally, other reported clinical or medical surveillance experiences have not identified any significant differences in responses between geriatric patients and younger patients.

While specific dosage adjustments for elderly patients are not indicated, healthcare providers should remain vigilant in monitoring this population for any potential adverse effects, given the general considerations for increased sensitivity in older adults.

Pregnancy

There are no adequate well-controlled studies of PULMICORT RESPULES in pregnant women. However, published studies on the use of budesonide, the active ingredient in PULMICORT RESPULES, indicate that inhaled budesonide does not increase the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study show no increased risk for congenital malformations associated with inhaled budesonide during early pregnancy, with rates of recorded congenital malformations being similar to those in the general population (3.8% vs. 3.5%, respectively). Additionally, the incidence of orofacial clefts in infants exposed to inhaled budesonide was comparable to the expected number in the normal population (4 children vs. 3.3, respectively).

Animal reproduction studies have demonstrated that budesonide, when administered subcutaneously, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at doses less than the maximum recommended human daily inhalation dose (MRHDID). However, these adverse effects were not observed in rats receiving inhaled doses approximately 2 times the MRHDID. In embryo-fetal development studies, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities in pregnant rabbits at doses 0.5 times the MRHDID, and similar adverse fetal effects were noted in pregnant rats at doses approximately 5 times the MRHDID. Conversely, no structural abnormalities or embryocidal effects were seen in another study in pregnant rats at doses approximately 2 times the MRHDID.

The estimated background risk of major birth defects and miscarriage in the U.S. general population is 2% to 4% and 15% to 20%, respectively. In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes, including preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Therefore, pregnant women with asthma should be closely monitored, and medication should be adjusted as necessary to maintain optimal asthma control.

There are no well-controlled human studies investigating the effects of PULMICORT RESPULES during labor and delivery. Given the potential risks associated with poorly controlled asthma during pregnancy, healthcare professionals should weigh the benefits of asthma control against the potential risks of budesonide therapy in pregnant patients.

Lactation

Budesonide has been shown to affect prenatal viability and the viability of pups at birth and during lactation in animal studies. Specifically, at doses of 20 mcg/kg/day and above, which is approximately 0.2 times the maximum recommended human dose on a mcg/m² basis, there was a noted decrease in maternal body-weight gain.

In a peri-and post-natal development study involving rats, budesonide did not impact delivery; however, it did adversely affect the growth and development of offspring. At doses less than 0.2 times the maximum recommended human dose and higher, there was a reduction in offspring survival, and surviving pups exhibited decreased mean body weights at birth and throughout lactation. These effects were observed alongside maternal toxicity.

Given these findings, healthcare professionals should exercise caution when considering the use of budesonide in lactating mothers, as potential risks to breastfed infants may exist.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Acute toxic effects following an overdose of PULMICORT RESPULES are considered to be low. However, it is important for healthcare professionals to be aware of the potential consequences associated with excessive use of inhaled corticosteroids over extended periods.

Potential Symptoms

In cases of prolonged excessive dosing, patients may experience systemic corticosteroid effects. These can include hypercorticism, which is characterized by symptoms such as weight gain, hypertension, and glucose intolerance. Additionally, growth suppression may occur in pediatric patients, necessitating careful monitoring of growth parameters.

Recommended Actions

In the event of suspected overdosage, it is advisable for healthcare providers to assess the patient's clinical status and consider the need for supportive care. Monitoring for signs of systemic corticosteroid effects is essential, particularly in patients who have been using high doses for an extended duration. If significant symptoms arise, appropriate management strategies should be implemented based on the clinical presentation.

Overall, while the risk of acute toxicity is low, vigilance is warranted to mitigate the potential adverse effects associated with chronic overuse of inhaled corticosteroids.

Nonclinical Toxicology

No teratogenic effects were observed in the studies conducted. Fertility and reproductive performance remained unaffected in rats at subcutaneous doses up to 80 mcg/kg, which is approximately equivalent to the maximum recommended human dose on a mcg/m² basis. However, at subcutaneous doses of 20 mcg/kg and above, approximately 0.2 times the maximum recommended human dose in adults on a mcg/m² basis, there was a noted decrease in prenatal viability and viability of pups at birth and during lactation, alongside a reduction in maternal body-weight gain. No adverse effects were recorded at a dose of 5 mcg/kg, which is approximately 0.05 times the maximum recommended human dose in adults on a mcg/m² basis.

In a two-year study involving Sprague-Dawley rats, budesonide resulted in a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg, approximately 0.5 and 0.1 times the maximum recommended human dose in adults and children aged 12 months to 8 years, respectively, on a mcg/m² basis. No tumorigenicity was observed in male rats at oral doses up to 25 mcg/kg, approximately 0.2 and 0.04 times the maximum recommended human dose in adults and children aged 12 months to 8 years, respectively, nor in female rats at oral doses up to 50 mcg/kg. In two additional two-year studies with male Fischer and Sprague-Dawley rats, budesonide did not induce gliomas at an oral dose of 50 mcg/kg. However, a statistically significant increase in the incidence of hepatocellular tumors was noted in male Sprague-Dawley rats at the same oral dose. The concurrent reference corticosteroids, prednisolone and triamcinolone acetonide, exhibited similar findings in these studies.

In a 91-week study in mice, budesonide did not demonstrate any treatment-related carcinogenicity at oral doses up to 200 mcg/kg, which is approximately equivalent to and 0.1 times the maximum recommended human dose in adults and children aged 12 months to 8 years on a mcg/m² basis. Furthermore, budesonide was not found to be mutagenic or clastogenic in six different test systems, including the Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, and DNA repair analysis in rat hepatocyte culture.

Postmarketing Experience

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported following the use of PULMICORT RESPULES. It is advised to discontinue PULMICORT RESPULES if such reactions occur.

There have been observations of immune system effects, indicating a higher likelihood of infections in patients using medications that may weaken the immune system. Symptoms of infection reported include fever, pain, aches, chills, fatigue, nausea, and vomiting. Healthcare providers should be informed of any signs of infection during treatment with PULMICORT RESPULES.

Cases of adrenal insufficiency have been noted, characterized by insufficient production of steroid hormones by the adrenal glands. Symptoms associated with adrenal insufficiency include fatigue, weakness, nausea, vomiting, and low blood pressure.

A decrease in bone mineral density has been reported, suggesting that healthcare providers may consider monitoring bone strength during treatment with PULMICORT RESPULES.

Instances of slowed or delayed growth have also been documented, prompting healthcare providers to monitor growth in pediatric patients receiving PULMICORT RESPULES.

Eye problems, including glaucoma and cataracts, have been reported. Healthcare providers may recommend regular eye examinations for patients using PULMICORT RESPULES.

Additionally, increased wheezing immediately following the administration of PULMICORT RESPULES has been observed. Patients are advised to have a fast-acting inhaled bronchodilator available to manage sudden wheezing episodes.

Patient Counseling

Patients should be advised that PULMICORT RESPULES must be administered using a jet nebulizer connected to a compressor that provides adequate airflow, equipped with either a mouthpiece or a suitable face mask. It is important to inform patients that ultrasonic nebulizers are not appropriate for the administration of PULMICORT RESPULES and should not be used.

Patients should be made aware of the potential for localized infections with Candida albicans in the mouth and pharynx. If oropharyngeal candidiasis occurs, it should be treated with appropriate local or systemic antifungal therapy while continuing PULMICORT RESPULES. However, therapy may need to be temporarily interrupted under close medical supervision. Patients are advised to rinse their mouths after inhalation to help mitigate this risk.

It is crucial to inform patients that PULMICORT RESPULES is not intended for the relief of acute asthma symptoms, and extra doses should not be used for this purpose. Acute symptoms should be managed with an inhaled, short-acting beta-agonist, such as albuterol. Patients should be instructed to notify their healthcare professional immediately if they experience any of the following: decreasing effectiveness of inhaled, short-acting beta-agonists; an increased need for inhalations of these medications; or a significant decrease in lung function as outlined by their physician.

Patients should not discontinue therapy with PULMICORT RESPULES without consulting their healthcare provider, as symptoms may recur upon discontinuation. They should also be informed about the risk of hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, and should discontinue use if such reactions occur.

For patients on immunosuppressant doses of corticosteroids, it is important to warn them to avoid exposure to chickenpox or measles. If exposure occurs, especially in children who have not had chickenpox or been properly vaccinated, they should consult their physician without delay. Patients should also be informed of the potential for worsening existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex.

Patients should be advised that PULMICORT RESPULES may lead to systemic corticosteroid effects, such as hypercorticism and adrenal suppression. They should be made aware that there have been reports of deaths due to adrenal insufficiency during and after transitioning from systemic corticosteroids. Therefore, patients should taper slowly from systemic corticosteroids when switching to PULMICORT RESPULES.

Patients at increased risk for decreased bone mineral density should be informed that the use of corticosteroids may further elevate this risk. Additionally, patients should be made aware that orally inhaled corticosteroids, including PULMICORT RESPULES, may reduce growth velocity in pediatric patients. Healthcare professionals should closely monitor the growth of children and adolescents receiving corticosteroids by any route.

Long-term use of inhaled corticosteroids may increase the risk of eye problems, such as cataracts or glaucoma; therefore, regular eye examinations should be considered. Patients should be instructed to use PULMICORT RESPULES at regular intervals, once or twice daily, as its effectiveness is contingent upon consistent use. Maximum benefit may not be realized for 4 to 6 weeks or longer after initiating treatment. If symptoms do not improve within this timeframe or if the condition worsens, patients should contact their healthcare professional.

Patients should be advised to rinse their child’s mouth with water and have them spit it out after each treatment with PULMICORT RESPULES, avoiding swallowing the water to reduce the risk of developing a fungal infection (thrush) in the mouth. If a child has been on long-term corticosteroids and the dose is being reduced or stopped, a warning card should be carried to indicate that the child may require corticosteroids during times of stress or during an asthma attack that does not respond to bronchodilator medications.

Healthcare providers may need to monitor the child’s blood, breathing, and conduct eye examinations while the child is using PULMICORT RESPULES.

Storage and Handling

PULMICORT RESPULES are supplied in a configuration that ensures optimal preservation of the product's integrity. They should be stored upright at a controlled room temperature of 20-25°C (68-77°F) and must be protected from light to maintain efficacy.

Once an envelope has been opened, the shelf life of the unused RESPULES ampules is limited to 2 weeks, provided they are returned to the aluminum foil envelope to shield them from light. It is imperative that any opened RESPULES ampule is used promptly. Additionally, freezing of the product is strictly prohibited to prevent degradation.

Additional Clinical Information

Patients using PULMICORT RESPULES should be advised to rinse their mouths after inhalation to minimize potential side effects. It is crucial for patients to contact their physician immediately if they experience asthma episodes that do not respond to their usual bronchodilator doses during treatment. Those who have previously been maintained on 20 mg or more per day of prednisone (or its equivalent) may be at increased risk for adrenal insufficiency when transitioning from systemic corticosteroids to inhaled corticosteroids. Therefore, patients should carry a medical identification card indicating the need for supplementary systemic corticosteroids during periods of stress or severe asthma attacks.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Pulmicort Respules as submitted by AstraZeneca Pharmaceuticals LP. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)