Pulmicort

Description

Budesonide, the active ingredient in PULMICORT FLEXHALER, 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, being practically insoluble in water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. The partition coefficient of budesonide between octanol and water at pH 7.4 is 1.6 x 10^3.

PULMICORT FLEXHALER is an inhalation-driven multi-dose dry powder inhaler that delivers a formulation containing 1 mg of micronized budesonide per actuation, along with micronized lactose monohydrate, which includes trace levels of milk proteins. Each actuation of PULMICORT FLEXHALER 180 mcg provides 160 mcg of budesonide from the mouthpiece, while each actuation of PULMICORT FLEXHALER 90 mcg delivers 80 mcg of budesonide. The PULMICORT FLEXHALER 180 mcg contains a total of 120 actuations, whereas the PULMICORT FLEXHALER 90 mcg contains 60 actuations.

Uses and Indications

PULMICORT FLEXHALER is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older.

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

For oral inhalation only.

In patients 18 years of age and older, the recommended starting dosage is 360 mcg administered twice daily. In certain adult patients, a starting dose of 180 mcg twice daily may be sufficient. The maximum dosage should not exceed 720 mcg administered twice daily.

For patients aged 6 to 17 years, the recommended starting dosage is 180 mcg administered twice daily. In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate. The maximum dosage for this age group should not exceed 360 mcg administered twice daily.

Healthcare professionals should ensure that patients are instructed on the proper inhalation technique to achieve optimal therapeutic effects.

Contraindications

Use of PULMICORT FLEXHALER is contraindicated in the following situations:

Patients requiring primary treatment for status asthmaticus or other acute episodes of asthma that necessitate intensive measures should not use this product. Additionally, individuals with severe hypersensitivity to milk proteins or any of the ingredients in PULMICORT FLEXHALER are contraindicated from its use due to the risk of severe allergic reactions.

Warnings and Precautions

Localized infections, particularly Candida albicans infections of the mouth and throat, may occur in patients using PULMICORT FLEXHALER. Healthcare professionals should monitor patients periodically for signs of adverse effects on the oral cavity. It is advisable to instruct patients to rinse their mouths following inhalation to mitigate this risk.

PULMICORT FLEXHALER is not indicated for the relief of acute asthma symptoms. In cases of rapidly deteriorating asthma, patients require immediate re-evaluation to ensure appropriate management.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported with the use of PULMICORT FLEXHALER. 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 FLEXHALER to these patients, as they may experience a more serious or even fatal course of chickenpox or measles.

When transferring patients from systemic corticosteroid therapy to PULMICORT FLEXHALER, there is a risk of impaired adrenal function. It is essential 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, the dosage of PULMICORT FLEXHALER should be reduced gradually.

Long-term administration of PULMICORT FLEXHALER may lead to a reduction in bone mineral density. Therefore, it is important to monitor patients who have major risk factors for decreased bone mineral content. Additionally, the growth of pediatric patients should be closely monitored during treatment.

Patients should be monitored for the development of glaucoma and cataracts, as these conditions may arise during treatment with PULMICORT FLEXHALER.

In rare instances, paradoxical bronchospasm may occur. If this happens, PULMICORT FLEXHALER should be discontinued, and alternative therapy should be initiated.

Healthcare professionals should remain vigilant for eosinophilic conditions and Churg-Strauss syndrome in patients receiving PULMICORT FLEXHALER.

To ensure patient safety, it is recommended to conduct regular laboratory tests to monitor bone mineral density in at-risk patients, assess the growth of pediatric patients, and perform close monitoring for glaucoma and cataracts.

Side Effects

Most common adverse reactions observed in patients using PULMICORT FLEXHALER include nasopharyngitis, nasal congestion, pharyngitis, allergic rhinitis, viral upper respiratory tract infections, nausea, viral gastroenteritis, otitis media, and oral candidiasis.

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 to mitigate this risk.

Patients should be cautioned that PULMICORT FLEXHALER is not intended for the relief of acute asthma symptoms. In cases of rapidly deteriorating asthma, immediate re-evaluation is necessary. Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been reported. If any of these reactions occur, discontinuation of PULMICORT FLEXHALER is advised.

Immunosuppression may occur, leading to a potential worsening of infections such as existing tuberculosis, fungal, bacterial, viral, or parasitic infections, as well as ocular herpes simplex. Caution is warranted when using PULMICORT FLEXHALER in patients with these infections. Additionally, susceptible patients may experience a more serious or even fatal course of chickenpox or measles.

When transferring patients from systemic corticosteroid therapy to PULMICORT FLEXHALER, there is a risk of impaired adrenal function. It is essential to taper patients slowly from oral steroids to minimize this risk. Hypercorticism and adrenal suppression may occur, particularly with very high dosages or at regular dosages in susceptible individuals. If such changes are observed, a gradual reduction of PULMICORT FLEXHALER is recommended.

Long-term administration of PULMICORT FLEXHALER may lead to a reduction in bone mineral density; therefore, patients with major risk factors for decreased bone mineral content should be monitored. Pediatric patients should have their growth monitored during treatment.

Close monitoring for glaucoma and cataracts is warranted in patients using PULMICORT FLEXHALER. Paradoxical bronchospasm has been reported; if this occurs, the medication should be discontinued, and alternative therapy should be instituted.

Healthcare providers should remain vigilant for eosinophilic conditions and Churg-Strauss syndrome in patients receiving PULMICORT FLEXHALER.

The potential for acute toxic effects following an overdose of PULMICORT FLEXHALER is low. However, the use of excessive doses (up to 6400 mcg daily) for prolonged periods may lead to systemic corticosteroid effects such as hypercorticism. Postmarketing experience indicates that acute overdose of inhaled budesonide commonly remains asymptomatic.

Drug Interactions

The concomitant use of strong Cytochrome P450 3A4 inhibitors, such as ritonavir, should be approached with caution. Co-administration 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, and dosage adjustments may be necessary based on the clinical response and tolerance of the patient.

Packaging & NDC

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

Pediatric Use

In a pivotal 12-week study, 204 pediatric patients aged 6 to 17 years were treated with PULMICORT FLEXHALER at a dosage of twice daily, demonstrating efficacy comparable to that observed in adults aged 18 years and older. The type and frequency of adverse events in this age group were similar to those reported in adult patients. However, the safety and effectiveness of PULMICORT FLEXHALER in asthma patients under 6 years of age have not been established.

Controlled clinical studies indicate that orally inhaled corticosteroids, including budesonide, may lead to a reduction in growth velocity among pediatric patients. This reduction has been noted even in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity may serve as a more sensitive indicator of systemic corticosteroid exposure than traditional HPA-axis function tests. The long-term implications of this growth reduction, including its impact on final adult height, remain uncertain, and the potential for "catch up" growth following discontinuation of treatment has not been adequately studied.

In a study involving asthmatic children aged 5 to 12 years, those treated with a different PULMICORT dry powder inhaler at a dose of 200 mcg twice daily experienced a 1.1-centimeter reduction in growth compared to a placebo group at the end of one year. Notably, this difference did not increase over three additional years of treatment, and by the end of four years, growth velocities were similar between the treatment and placebo groups. However, the conclusions of this study may be confounded by unequal corticosteroid use among treatment groups and the inclusion of patients who entered puberty during the study.

The administration of inhaled budesonide via a different PULMICORT dry powder inhaler at doses up to 800 mcg/day or via a pressurized metered-dose inhaler at doses up to 1200 mcg/day in 216 pediatric patients aged 3 to 11 years for 2 to 6 years showed no significant effect on statural growth compared to 62 matched control patients receiving non-corticosteroid therapy. Nonetheless, the long-term effects of inhaled budesonide on growth are not fully understood.

Monitoring of growth in pediatric patients receiving orally inhaled corticosteroids, including PULMICORT FLEXHALER, is recommended, utilizing methods such as stadiometry. If growth suppression is observed in a child or adolescent on corticosteroids, it is important to consider their potential sensitivity to this effect. The benefits of prolonged treatment should be carefully weighed against the potential growth effects, and each patient should be titrated to the lowest effective dose to manage their asthma while minimizing systemic effects.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were included in controlled clinical studies of inhaled budesonide, with a total of 153 patients in this age group, including 11 treated with PULMICORT FLEXHALER. Among these, one patient was 75 years of age or older. Overall, no significant differences in safety were observed between elderly patients and their younger counterparts. However, the clinical studies did not enroll a sufficient number of patients aged 65 years and over to adequately assess differences in efficacy between these groups.

Additionally, other clinical or medical surveillance experiences have not indicated any notable differences in responses to treatment between elderly and younger patients. Given the potential for altered pharmacokinetics and pharmacodynamics in geriatric patients, it is recommended that dose selection for elderly patients be approached with caution. Typically, initiating treatment at the lower end of the dosing range is advisable, taking into account the increased likelihood of diminished hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies. Regular monitoring and assessment of the patient's response to therapy are also recommended to ensure safety and efficacy in this population.

Pregnancy

There are no adequate well-controlled studies of PULMICORT FLEXHALER in pregnant women. However, published studies on the use of budesonide, the active ingredient in PULMICORT FLEXHALER, exist. In animal reproduction studies, budesonide has been associated with structural abnormalities, embryocidal effects, and reduced fetal weights in rats and rabbits at doses less than the maximum recommended human daily inhalation dose (MRHDID). Notably, these adverse effects were not observed in rats receiving inhaled doses approximately 2 times the MRHDID.

Clinical studies involving pregnant women have not demonstrated an increased risk of congenital malformations associated with inhaled budesonide when administered during pregnancy. The rate of recorded congenital malformations in these studies was comparable to the general population rate (3.8% vs. 3.5%). Additionally, the incidence of orofacial clefts among infants exposed to inhaled budesonide was similar to the expected number in the general population (4 cases vs. 3.3). In a study of 2,534 infants whose mothers were exposed to inhaled budesonide, the rate of congenital malformations was not significantly different from that of all newborns during the same period (3.6%).

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, 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.

While there are no well-controlled human studies investigating the effects of PULMICORT FLEXHALER during labor and delivery, it is important to note that experience with oral corticosteroids suggests that rodents may be more susceptible to structural abnormalities from corticosteroid exposure than humans. In animal studies, budesonide caused a decrease in prenatal viability and viability in pups at birth and during lactation at doses 0.1 times the MRHDID. In an embryo-fetal development study in pregnant rabbits, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.3 times the MRHDID. Similarly, in pregnant rats, budesonide produced adverse fetal effects at doses approximately 4 times the MRHDID, while no structural abnormalities or embryocidal effects were observed at doses approximately 2 times the MRHDID. Budesonide did not affect delivery but did impact the growth and development of offspring, resulting in reduced survival and decreased mean body weights at birth and during lactation at doses 0.1 times the MRHDID and higher.

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 0.1 times the maximum recommended human dose (MRHDID) on a microgram per square meter (mcg/m²) basis, maternal subcutaneous doses of 20 mcg/kg/day and above resulted in decreased maternal body-weight gain and reduced offspring survival.

In a peri-and post-natal development study involving rats, budesonide did not impact delivery; however, it adversely affected the growth and development of the offspring. At doses of 0.1 times the MRHDID and higher, there was a noted decrease in mean body weights at birth and during lactation, alongside reduced survival rates of the offspring. These effects were observed in conjunction with maternal toxicity.

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

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

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 outlined 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 overdose of PULMICORT FLEXHALER is associated with a low potential for toxic effects. However, when excessive doses are administered over extended periods, there is a risk of systemic corticosteroid effects, notably hypercorticism.

Clinical studies have demonstrated that the administration of another budesonide-containing dry powder inhaler at a dosage of 3200 mcg daily for six weeks resulted in a significant reduction of 27% in the plasma cortisol response to a 6-hour infusion of ACTH, compared to a placebo group, which exhibited a +1% change. In comparison, a daily dose of 10 mg prednisone led to a 35% reduction in the plasma cortisol response to ACTH.

Postmarketing surveillance indicates that acute overdose of inhaled budesonide frequently remains asymptomatic. Nevertheless, the use of excessive doses, reaching up to 6400 mcg daily over prolonged durations, has been associated with systemic corticosteroid effects, including hypercorticism.

In the event of an overdose, it is recommended that healthcare professionals monitor the patient for any signs of systemic corticosteroid effects and manage symptoms accordingly. Regular assessment of plasma cortisol levels may be warranted in cases of prolonged excessive dosing to evaluate the impact on adrenal function.

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 0.5 times the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m² basis. However, at a subcutaneous dose of 20 mcg/kg/day, approximately 0.1 times the MRHDID on a mcg/m² basis, decreases in maternal body weight gain, prenatal viability, and the viability of the young at birth and during lactation were noted. No such adverse effects were observed at a dose of 5 mcg/kg, approximately 0.03 times the MRHDID on a mcg/m² basis.

In a 104-week oral study involving Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was noted in male rats receiving an oral dose of 50 mcg/kg/day, approximately 0.3 times the MRHDID on a mcg/m² basis. No tumorigenicity was observed in male rats at oral doses up to 25 mcg/kg, approximately 0.2 times the MRHDID, and in female rats at doses up to 50 mcg/kg, approximately 0.3 times the MRHDID. 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 observed in male Sprague-Dawley rats at the same dose. The concurrent reference corticosteroids, prednisone and triamcinolone acetonide, exhibited similar findings in these studies.

There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day, approximately 0.7 times the MRHDID on a mcg/m² basis. Additionally, 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

Postmarketing experience with PULMICORT FLEXHALER has identified several adverse events reported voluntarily or through surveillance programs.

Hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, have been documented. Localized infections caused by Candida albicans have been observed in the mouth and pharynx in some patients. There is an association with immune system effects, indicating a higher likelihood of infections in individuals taking medications that may weaken the immune system.

Adrenal insufficiency has been reported, characterized by symptoms such as tiredness, weakness, nausea, vomiting, and low blood pressure. Additionally, a decrease in bone mineral density has been noted, warranting regular monitoring by healthcare providers during treatment.

In pediatric populations, there have been reports of slowed or delayed growth, necessitating regular assessments of growth in children using PULMICORT FLEXHALER. Eye problems, including glaucoma and cataracts, have also been reported, highlighting the importance of regular eye examinations during treatment.

Furthermore, instances of increased wheezing immediately following the use of PULMICORT FLEXHALER have been documented, emphasizing the need for patients to have a short-acting beta-agonist (rescue inhaler) available to manage sudden wheezing episodes.

Patient Counseling

Patients being treated with PULMICORT FLEXHALER should receive comprehensive information and instructions to ensure the safe and effective use of the medication. Healthcare providers should emphasize the importance of reading and following the accompanying FDA Approved Patient Labeling for proper use and to achieve maximum improvement.

Patients should be advised of the potential for localized infections with Candida albicans in the mouth and pharynx. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic antifungal therapy while continuing therapy with PULMICORT FLEXHALER. However, therapy may need to be temporarily interrupted under close medical supervision. Rinsing the mouth with water after inhalation is strongly recommended to reduce the risk of such infections.

It is crucial to inform patients that PULMICORT FLEXHALER 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, which the physician should provide along with instructions for its use.

Patients must be instructed to notify their physician immediately if they experience any of the following: a decrease in the 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 the physician. Additionally, patients should not discontinue therapy with PULMICORT FLEXHALER without consulting their healthcare provider, as symptoms may recur upon discontinuation.

Healthcare providers should inform patients about the risk of hypersensitivity reactions, including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm, associated with PULMICORT FLEXHALER. Patients should be advised to discontinue the medication if such reactions occur.

Patients should be made aware that PULMICORT FLEXHALER contains small amounts of lactose, which may contain trace levels of milk proteins. This could potentially lead to cough, wheezing, or bronchospasm in patients with a severe milk protein allergy.

For patients on immunosuppressant doses of corticosteroids, it is important to warn them to avoid exposure to chickenpox or measles and to consult their physician immediately if exposed. They should also be informed about the potential worsening of existing infections, including tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Patients should be advised that PULMICORT FLEXHALER may cause systemic corticosteroid effects, such as hypercorticism and adrenal suppression. They should be informed 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 FLEXHALER.

Those at increased risk for decreased bone mineral density should be cautioned that the use of corticosteroids may further elevate this risk. Additionally, patients should be informed that orally inhaled corticosteroids, including budesonide inhalation powder, may reduce growth velocity in pediatric patients, necessitating close monitoring of growth in children and adolescents.

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 FLEXHALER at regular intervals, as its effectiveness relies on consistent use. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. If symptoms do not improve or worsen during this period, patients should contact their physician.

Healthcare providers should ensure that patients are carefully instructed on the proper use of PULMICORT FLEXHALER to guarantee optimal dose delivery. Patients may not sense the medication entering their lungs during inhalation, but this does not indicate that the medication was not delivered. They should not repeat their inhalation if they do not feel the medication.

Patients should rinse their mouths with water and spit it out after each dose of PULMICORT FLEXHALER to minimize the risk of developing a fungal infection (thrush) in the mouth. They should also be reminded to always have a short-acting beta-agonist on hand for use in case of breathing problems between doses of PULMICORT FLEXHALER or during a sudden asthma attack. Patients should contact their healthcare provider immediately if their short-acting rescue medication does not effectively relieve asthma symptoms, if they need to use it more frequently than usual, or if their breathing problems worsen while using PULMICORT FLEXHALER.

Finally, patients who have been on long-term corticosteroid therapy and are now reducing or stopping their dose should carry a medical alert card. This card should indicate that they may require increased corticosteroids during times of stress or in the event of an asthma attack that does not improve with bronchodilator medications.

Storage and Handling

The PULMICORT FLEXHALER inhaler is supplied in a configuration that cannot be refilled and must be discarded once empty. It is essential to store the inhaler in a dry place at a controlled room temperature of 20-25°C (68-77°F), in accordance with USP guidelines, ensuring that the cover remains tightly in place.

To maintain safety, the inhaler should be kept out of the reach of children. Additionally, if the inhaler is used beyond the point where the zero mark reaches the middle of the window, the correct dosage of medication may not be delivered, necessitating the disposal of the unit.

Additional Clinical Information

Patients using PULMICORT FLEXHALER should be advised to rinse their mouth 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. For those transitioning from oral corticosteroids, a gradual weaning from systemic corticosteroid use is recommended. Additionally, patients should carry a medical identification card indicating their need for supplementary systemic corticosteroids during times of stress or severe asthma attacks.

FDA Insert (PDF)

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

View full prescribing information (PDF)