What Factors Affect a Sufficient Budesonide Dose?

Budesonide suspension for inhalation, the indication is for the treatment of bronchial asthma. Can replace or reduce oral steroid therapy. It is recommended that inhaled budesonide suspensions be used when steroid therapy is not appropriate in other ways.

Budesonide suspension for inhalation, the indication is for the treatment of bronchial asthma. Can replace or reduce oral steroid therapy. It is recommended that inhaled budesonide suspensions be used when steroid therapy is not appropriate in other ways.

Drug Name

Budesonide suspension for inhalation

Drug type

Prescription drugs, medicines for medical workers' injuries

Special medicine

Doping

Use classification

Adrenal corticosteroids

Budesonide suspension ingredients for inhalation

Main ingredient: Budesonide Chemical name: 16, 17-22R, S-propylmethylenedioxo-progestin-1,4-diene-11, 21-dihydroxy-3,20-dione.
The structural formula is:

Molecular formula: C ₂₅ H ₃₄ O ₆
Molecular weight: 430.5

Properties of Budesonide Suspension for Inhalation

This product is a fine particle suspension, fine particles precipitate after standing, and shake into a white or off-white suspension.

Indications for budesonide suspension for inhalation

Treatment of bronchial asthma.
Can replace or reduce oral steroid therapy.
It is recommended that inhaled budesonide suspensions be used when steroid therapy is not appropriate in other ways.

Budesonide suspension specifications for inhalation

(1) 0.5 mg / 2 ml (2) 1 mg / 2 ml

Budesonide Suspension for Inhalation

For details, please refer to "[Introduction to Use]"
Budesonide Suspension for Inhalation < br If asthma exacerbates, the number and / or total dose of budesonide needed to be increased each day.
Budesonide suspension for inhalation should be administered via a suitable nebulizer. According to different nebulizers, the actual inhaled dose of the patient is 40-60% of the indicated amount. The atomization time and output dose depend on the flow rate, nebulizer volume, and liquid volume. For most nebulizers, a suitable liquid volume is 2 to 4 ml.
Inhalation of the budesonide suspension may cause some deposition during storage. If, after shaking, a completely stable suspension cannot be formed, it should be discarded.
Starting dose, severe asthma or reduced dose of oral glucocorticoids <br /> Adults: 1-2 mg once, twice a day.
Children: 0.5 1mg once, twice a day.
Maintenance dose < br The maintenance dose should be individualized and should be the lowest dose that keeps patients asymptomatic. Suggested dose:
Adult: 0.5 1mg once, twice a day.
Children: 0.25 to 0.5 mg once, twice a day.
Guidance to patients Patients must be informed that budesonide is a preventative medication that must be used routinely and should not be used alone as a relief for acute asthma attacks.
2. Taking individual needs into consideration, instruct patients to use Budesonide Suspension for Inhalation according to their individual situation. Each package should be accompanied by a complete instruction manual.
3 For patients who are concurrently inhaled with bronchodilators, it is recommended that bronchodilators be used prior to use of budesonide to increase the amount of budesonide entering the bronchial tree. Allow a few minutes between the two inhalants.
Clinical management Non-oral corticosteroid-dependent patients <br /> are treated with the recommended dose of budesonide and generally have a therapeutic effect within 10 days.
For patients with excessive mucus secretions in the trachea, short-term (about 2 weeks) oral corticosteroid treatment should be given while using budesonide, starting with high doses and gradually reducing, and at least one month of continuous treatment should be given. Determine the maximum effect that a given dose of budesonide can achieve.
2. Patients who are dependent on oral corticosteroids <br Patients who are dependent on oral corticosteroids need to be particularly careful when switching to inhaled budesonide suspension because of chronic hypocorticoid-pituitary-adrenal dysfunction caused by long-term oral corticosteroid treatment Recovery is slow.
Budesonide treatment should be started when the patient's asthma is relatively stable. You must combine high-dose budesonide with the original dose of oral steroids for about 2 weeks, and then gradually reduce the oral steroid dose (for example, reduce 1 mg of prednisolone every 4 days or equivalent dose of other oral steroids, but reduce the The rate should be individualized depending on the clinical response) to the lowest possible dose. The patient should not change the amount of budesonide while continuing oral steroids.
In many cases, it is possible to completely replace oral corticosteroids with inhaled budesonide. Some patients require low-dose oral steroids. Some patients may feel uncomfortable withdrawing oral corticosteroids because the systemic effects of corticosteroids are reduced and doctors need to support the patient, emphasizing the reason for treatment with budesonide.
It can take a long time for the body to regain sufficient natural corticosteroids, as long as 12 months. Patients who switch to budesonide should bring a warning card indicating that they may need additional systemic corticosteroids during an emergency, such as severe infections, trauma or surgery, in which case additional oral corticosteroids may be required.
The transition from oral therapy to the use of inhaled budesonide suspensions may show signs of low systemic steroid effects. Early allergic symptoms may recur (eg rhinitis, eczema, and conjunctivitis), and patients may experience fatigue, headaches, muscle and joint pain or occasional nausea and vomiting. In these cases, further medical measures are required.
Compatible < br Budesonide suspension for inhalation can be mixed with 0.9% saline and terbutaline, salbutamol, sodium cromoglycate or ipratropium bromide.
Compatibility taboos < br has not been reported so far.

Adverse effects of budesonide suspension for inhalation

The following adverse reactions have been reported in pediatric patients treated with inhaled budesonide suspension.
The incidence of common adverse reactions is based on three double-blind, placebo-controlled clinical studies conducted in the United States, with a total of 945 patients aged 12 months to 8 years (98 patients aged 12 months to 2 years and 2 to 4 years old) 225 patients and 622 patients aged 4 to 8 years) received inhaled budesonide suspension (0.25 to 1 mg daily for 12 weeks) or placebo.
The incidence and nature of adverse events in the inhaled budesonide suspension group were comparable to those of the placebo group. The table below shows the incidence of adverse events in studies conducted in the United States without considering the effects of previous bronchodilator and / or inhaled glucocorticoid therapy. The sample included 605 male patients and 340 female patients.

The following are all adverse events that occurred in at least one of the drug treatment groups at a rate of 3% or more and had an incidence in the inhaled budesonide suspension group that was comparable to or lower than the placebo group: fever, sinusitis , Pain, pharyngitis, bronchospasm, bronchitis, and headache.
Incidence rate is 1% to 3% (by body system)
The following information includes all adverse events with a incidence between 1 and 3%. At least one inhaled budesonide suspension treatment group had a higher incidence than comfort without considering its relevance to drug therapy. Adverse events in the drug group.
Systemic reactions: allergic reactions, chest pain, fatigue, flu-like symptomsRespiratory system: Impaired wheezing defense mechanisms: Herpes simplex, infection of the external ear, infected central and peripheral nervous systems: difficulty speaking, excessive movement of skin and skin appendages: eczema, pus Herpes, pruritus, hearing and vestibules: ear pain, vision: eye infections, psychiatry: anorexia, mood disorders, musculoskeletal system: fractures, myalgia Medication site: contact dermatitis platelets, bleeding and coagulation: purpuric white blood cells and resistance: neck Lymphadenopathy In three open studies, 447 asthmatic children who received inhaled budesonide suspension (average total daily dose of 0.5-1 mg) and 223 children who received traditional treatment of asthma were poor. Incidence rates are close.
In the published literature, the results of long-term open clinical trials, or post-market reports of all inhaled budesonide preparations worldwide, occasional adverse events (<1%) include: rapid or delayed allergies, including rashes , Contact dermatitis, urticaria, angioedema, and bronchospasm; symptoms of hypoadrenal cortex and hyperadrenal function; glaucoma, cataracts; psychiatric symptoms, including depression, aggressive reactions, irritability, anxiety, and mental illness; and bone Diseases, including ischemic necrosis of the femoral head and osteoporosis.
Budesonide is well tolerated. Most adverse reactions are mild. And it is local. Systemic effects and oropharyngeal complications caused by budesonide are dose-dependent.

Inhalation of budesonide suspension

People who are allergic to budesonide or any other ingredient.

Precautions for inhaled budesonide suspension

General matters Use with caution by athletes.
2. During steroid withdrawal, some patients may experience symptoms related to oral steroid withdrawal, such as joint and / or muscle pain, burnout, and depression, even if their respiratory function can be maintained or even improved.
3 Because budesonide can enter the circulatory system, systemic activity may occur especially at higher doses, so when taking more than the recommended dose of inhaled budesonide suspension (see [Usage and Dosage]), or during treatment Without titration to the lowest effective dose, HPA inhibition may occur. Because individuals have different sensitivities to the effects of cortisol production, physicians should consider this information when prescribing budesonide suspensions.
4 Because of the potential for systemic absorption of inhaled steroids, any systemic steroid effects appearing in patients treated with inhaled budesonide suspension should be observed. Patients with postoperative or adrenal insufficiency need close observation.
5. During treatment, a small number of patients may experience some systemic steroid effects, such as hyperadrenal function, decreased bone density, and adrenal depression, especially when treated with higher doses. If such a change occurs, the use of budesonide suspension for inhalation should be gradually reduced. This withdrawal plan is in accordance with the accepted procedures for the management of asthma symptoms and a systemic steroid reduction strategy.
6. The potential effects of sustained treatment with inhaled budesonide suspension on the growth rate of children need to be weighed against the clinical benefits and risks of alternative treatment options. In order to minimize the systemic effects of inhaled steroids, including promiclotin, each patient receiving treatment should be titrated to his / her lowest effective dose (see [Cautions] and [Children's Medication]).
7. Although in clinical studies, patients have been treated with inhaled budesonide suspensions for up to 1 year, the local and systemic effects of long-term use in humans are not fully understood. In particular, the effects of long-term use on the development or immunity of the mouth, pharynx, trachea, and lungs are unknown.
8. In clinical studies, some patients developed localized Candida albicans infections of the mouth and throat. The incidence was similar in the inhaled budesonide suspension treatment group and the placebo control group. If such infections occur, appropriate antifungal therapy and / or discontinuation of inhaled budesonide suspension may be required.
9. Patients with active or inactive tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or herpes simplex eyes need to be cautious.
10 After inhaled steroid treatment, rare cases of glaucoma, elevated intraocular pressure, and cataracts were reported.
11. Special care is required for patients who switch from systemic steroids to inhaled steroids, as there have been deaths due to adrenal insufficiency during or after inhaled steroids that changed from systemic steroids to systemic. When systemic steroids are discontinued, recovery of HPA axis function usually takes months. Patients who were treated with prednisone (or equivalent steroids) at a dose of 20 mg or more the previous day were most affected, especially when systemic steroids were completely withdrawn.
12. During HPA-axis suppression, patients may experience symptoms or signs of adrenal insufficiency when they experience trauma, surgery, infection (especially gastroenteritis), or other conditions related to severe electrolyte loss. Although inhaled budesonide suspension can control asthma symptoms under the above circumstances, at the clinically recommended dose, it cannot provide normal physiological amounts of steroids and mineralocorticoid activity in response to emergencies. Patients need additional oral steroids during stress reactions or severe asthma attacks. It is recommended that these patients carry warning cards with them.
13. Patients who switch from oral steroids to inhaled budesonide suspensions should be withdrawn slowly. During withdrawal, patients should be closely monitored for lung function (FEV1 or AMPEF), beta-agonist use, and asthma symptoms. In addition, symptoms related to adrenal insufficiency need to be observed, such as fatigue, burnout, weakness, nausea and vomiting, and hypotension.
14. Patients who have previously received high-dose systemic steroid treatment may experience early allergic symptoms or other immune system disorders such as rhinitis, conjunctivitis, erythrocytic abnormalities, eczema, and arthritis when switching from oral to budesonide .
15. Patients who use immunosuppressive drugs are more likely to develop infections than healthy individuals. For example, for sensitive patients using immunosuppressive steroids, the onset of chickenpox or measles is more severe and even fatal. Children or adults who have not had these diseases or have not been immunized should avoid such infections. How the dose, route, and duration of steroid therapy affect the risk of infection is unclear. The impact of underlying disease and / or previous steroid therapy on the risk of infection in patients is also unclear.
16. No study of patients with chickenpox and measles infection receiving inhaled steroids has been performed. A clinical study examined the immune response of children with asthma between 12 months and 8 years of age after receiving inhaled budesonide mixture (see section [Children's Medication]).
17. Patients receiving immunosuppressant steroid exposure to the source of varicella virus infection may require varicella-zoster immunoglobulin (VZIG) or mixed intravenous drip immunoglobulin (IVIG) treatment.
If the patient is exposed to the source of the measles virus infection, a mixed intramuscular injection of immunoglobulin (IG) may be needed for preventative treatment. (For a detailed description of the prescribing information for VZIG and IG, see their drug instructions).
18. Budesonide is not a bronchodilator and should not be used for rapid relief of acute bronchospasm or other acute asthma attacks.
19. When used concurrently with other inhaled asthma medications, bronchospasm may occur after taking the medication, accompanied by an immediate exacerbation of wheezing. If acute bronchospasm occurs after administration of budesonide suspension for inhalation, immediate treatment with a fast-acting inhaled bronchodilator must be used, interrupted inhalation of budesonide suspension, and other alternative treatment options .
20. During the treatment of inhaled budesonide suspension, if your asthma does not respond to the usual amount of bronchodilator in the patient, you should contact your doctor immediately.

Budesonide suspension for inhalation medication for pregnant and lactating women

Drugs for pregnant women < br Teratogenic effects : The FDA classifies them as pregnancy safety class BBudesonide, like other corticosteroids, is teratogenic and embryotoxic to rabbits and rats. In one study, rabbits received 25ugug / kg (based on ug / m ² , which is lower than the maximum recommended daily inhalation dose for adults), and rats received 500ug / kg (based on ug / m ² , which is about the maximum recommended for adults). (4 times the daily inhaled dose) is administered subcutaneously, resulting in a reduction in fetuses and a reduction in the weight of the pups. In another study on rats, no drug-induced effects were observed after inhalation at a dose of 250 ug / kq (based on ug / m ² , which is approximately twice the maximum recommended daily inhalation dose for adults). Teratogenesis and embryo toxicity.
Compared to humans, rodents are more susceptible to the carcinogenic effects of steroids.
In studies of pregnant women, there is no data to prove that inhaled budesonide increases the risk of fetal malformations during pregnancy.
In a large-scale prospective cohort epidemiological survey, three data from Sweden covering about 99% of pregnant women between 1995 and 1997 (ie Swedish medical birth records, congenital malformations registration, and childhood heart disease) were examined. Registration),
The results showed that the use of inhaled budesonide in early pregnancy did not increase the risk of fetal congenital malformations. Congenital malformations were performed on 2014 infants who had used inhaled budesonide to treat asthma during the first trimester of pregnancy (usually 10-12 weeks after the date of the last menstrual period, which is considered to be the most prone to major organ deformities) In the study, the incidence of congenital malformations was close to that of the total population (3.8% and 3.5%, respectively), and the number of infants with orofacial deformities was close to the expected number of normal populations (4 and 3.3, respectively). ).
The above data in another study involving 2,534 infants whose mothers had used inhaled budesonate did not differ from the incidence of congenital malformations in all newborns at the same time (3.6%).
With the exception of findings in animal studies, the possibility of fetal harm caused by medication during pregnancy is extremely low. However, human studies have not completely ruled out the possibility of harm, and budesonide for inhalation should only be used during pregnancy when it is really necessary.
Non-teratogenic effects :
Adrenal insufficiency may occur in newborns after the mother receives steroid treatment during pregnancy. Such infants should be closely monitored.
In animal studies, budesonide was found to penetrate the placental barrier.
Like other steroid hormones, embryonic development has been found in rabbits and rats after subcutaneous administration of budesonide. Similar effects were seen in rats after inhalation. The relevance of these findings to humans has not been determined. The results of a large number of prospective epidemiological studies and worldwide post-marketing experience have not found that inhaled budesonide during pregnancy can have adverse effects on embryos and newborns. As with other drugs, the use of budesonide during pregnancy should weigh its benefits to the mother and its possible risks to the embryo.
Medication for lactating women <br /> Like other steroids, budesonide can be secreted into human milk. Relevant data for budesonide dry powder inhalants show that the total daily oral budesonide intake of infants through milk is about 0.3% -1% of mothers. No studies have been conducted on lactating women using inhaled budesonide suspensions; however, it is expected that infants will also obtain a certain percentage of budesonide from their mothers through breast milk. Therefore, breastfeeding women can only be treated with inhaled budesonide suspension when clinical treatment is needed. Physicians need to weigh the benefits of breastfeeding to mothers and infants against the potential risks of infant exposure to traces of budesonide.

Budesonide suspension for inhalation for children

See [Usage and Dosage]
The safety of medication in infants between 6 and 12 months has been evaluated and the safety and effectiveness of medication in children between 12 months and 8 years of age have been determined (see [ Pharmacology and Toxicology ] and [Adverse Effects]).
A 12-week clinical study was performed in 141 children with mild to moderate asthma or recurrent / persistent wheezing at 6-12 months. All patients were randomized to receive a 0.5 mg or 1 mg inhaled budesonide suspension or placebo once daily. At the beginning and end of the trial, the ACTH stimulation test was used to evaluate the adrenal axis function of the patients, and the average change from baseline of the inhaled budesonide suspension treatment group and the placebo group was compared. The results showed that the patient's adrenal function was not Suppressed. Individually, 7 patients in this study (6 in the inhaled budesonide suspension group and 1 in the placebo group) experienced abnormal cortisol at 12 weeks from normal baseline stimulation of cortisol levels. Horizontal drift (see [ Pharmacology and Toxicology ]). Compared with patients in the placebo group, more patients with pneumonia were observed in the inhaled budesonide suspension treatment group. The inhaled budesonide suspension 0.5mg, 1mg, and placebo group were 2, 1 and 0 people.
The growth and development of children treated with inhaled steroids, including inhaled budesonide suspensions, should be monitored regularly. The potential benefits of sustained drug use on growth and development should be weighed against the clinical benefits and risks of treatment with inhaled budesonide suspension, combined with the benefits of alternative treatments. To minimize the systemic effects of inhaled steroids, including inhaled budesonide suspension, each patient should be titrated gradually to his / her lowest effective dose.
In an open-label, non-randomized clinical study, the immune response to varicella vaccine was measured in 243 asthma patients aged 12 months to 8 years who received 0.25 mg to 1 mg of budesnab for inhalation daily German suspension (n = 151) or nonsteroidal asthma treatment (n = 92) (ie ₂ -receptor agonist, leukotriene receptor antagonist, nidomimir). The percentage of patients who developed a serum protective antibody titer 5.0 (gpELISA value) in response to vaccination was similar to the inhaled budesonide suspension treatment group (85%) and the noncorticosteroid treatment group (90%). Childhood patients treated with inhaled budesonide suspension did not develop chickenpox due to vaccination.

Budesonide suspension for inhalation

Same as Adult [Dosage and Administration]
In three clinical trials of inhaled budesonide suspensions in adult patients, 65 (30%) of all 215 patients were 65 years of age or older and 22 (10%) were 75 years of age or older. These patients had no difference in safety indicators compared to younger patients. Other clinical reports or medical observations have not found differences in elderly patients and younger patients.

Budesonide Suspension for Inhalation Drug Interactions

In clinical studies, co-administration of budesonide with other drugs is more common, increasing the incidence of adverse events. Budesonide, as well as other steroid drugs, is mainly metabolized by cytochrome P450 (CYP) 3A4 (CYP3A4). Oral ketoconazole, a potent CYP3A4 inhibitor, results in an increase in the mean plasma drug concentration of oral budesonide. When combined with other known CYP3A4 inhibitors (such as itraconazole, clarithromycin, erythromycin, etc.), budesonide's metabolism may be inhibited, and budesonide's systemic exposure may be increased. Care should be taken when taking budesonide in combination with long-term ketoconazole or other known inhibitors of CYP3A4. Omeprazole has no effect on the pharmacokinetics of oral budesonide, whereas cimetidine (a major inhibitor of CYP1A2) can cause a slight decrease in budesonide clearance and a corresponding increase in oral bioavailability.

Overdose of budesonide suspension for inhalation

The probability of acute toxicity following overdose of budesonide suspension for inhalation is very low. If inhaled steroids are used excessively for a long time, systemic steroid effects such as hyperadrenal function or growth inhibition will occur (see [Cautions]).
The minimum lethal inhaled dose of the drug counterpart mouse is 100 mg / kg (in terms of body surface area, approximately 410 or 120 times the maximum daily recommended inhaled dose for adults or children, respectively). For rats, no animal death occurred when the inhaled dose reached 68 mg / kg (approximately 550 or 160 times the maximum daily recommended inhaled dose for adults or children, respectively, in terms of body surface area). The minimum oral lethal dose for mice is 200 mg / kg (in terms of body surface area, approximately 810 or 240 times the maximum daily recommended inhaled dose for an adult or child, respectively). The minimum oral lethal dose in rats is less than 100 mg / kg (in terms of body surface area, approximately 810 or 240 times the maximum daily recommended inhaled dose for adults or children, respectively).

Clinical trial of budesonide suspension for inhalation

Three 12-week, double-blind, placebo-controlled, parallel, randomized clinical studies of 1018 patients in the United States between 6 and 8 years of age with persistent asthma of varying duration (2-107 months) and severity Performed in children. The treatment groups were dosed once or twice daily at 0.25 mg, 0.5 mg, and 1 mg, respectively, compared with the placebo group to provide information on the doses administered at different asthma severity levels. In the above three clinical studies, patients applied a budesonide suspension for inhalation using a Pari-LC enhanced nebulizer (using a mask or nozzle) connected to a Pari Master compressor. The primary endpoint of the study was the nocturnal and daytime asthma symptom score (grades 0-3). The 5 doses below may have been studied in only one or two trials.
Three performed in 946 children aged 12 months to 8 years, recommended doses of budesonide suspension for inhalation (0.25mg-0.5mg, once or twice daily, up to the total daily dose The results of the 1 mg) clinical trial are given below. Compared with placebo, inhaled budesonide suspension 0.25mg once daily (1 trial), 0.25mg twice daily, and 0.5mg twice daily can be significant Reduce day and night scores for asthma symptoms. At 1 mg, once a day, and 0.5 mg, once a day (1 test), this product can significantly reduce the night or day asthma symptom score, but failed to reduce both. Relief of symptoms in response to treatment with inhaled budesonide is present in patients of different genders and ages. At all doses studied, inhaled budesonide suspension significantly reduced patients' need for bronchodilators. Analysis of a subgroup of patients who were able to complete a lung function test showed that improvement in lung function was related to inhaled budesonide suspension treatment. Compared with the placebo group, the patient's FEV1 [see Budesonide suspension for inhalation 0.5 mg, once daily dose group and 1 mg, once daily dose group (1 trial), 0.5 mg, daily The twice-administered group] and the morning PEF [1mg of this product, once-daily administration group (1 test); Significant improvement.
The asthma day and night symptom score (grades 0-3) showed a numerical decrease in 2-8 days, while the maximum treatment benefit was not reached by 4-6 weeks after starting treatment; night and day asthma symptoms The reduction in scores persisted throughout the 12-week period of the double-blind trial.
Patients who have not received inhaled corticosteroid therapy < br Budesonide inhalation suspensions 0.25mg, 0.5mg, and 1mg, the therapeutic effect of the daily dose is 344, aged 12 months to 8 years Between children with mild to moderate persistent asthma (the average baseline nocturnal asthma symptom score in the treatment group ranged from 1.07 to 1.34) and could not be controlled by bronchodilator alone. The change in the nocturnal asthma symptom score from baseline to 0-12 weeks is shown in Figure 1. Compared with the placebo group, patients treated with this product showed a statistically significant improvement in the nighttime asthma symptom score. A similar improvement was observed in the daytime asthma symptom score.

Patients who have previously been treated with inhaled corticosteroids <br /> Efficacy of inhaled budesonide suspensions at 0.25mg and 0.5mg twice daily at 133 patients aged 4-8 years In between, children with asthma who had previously been treated with inhaled corticosteroids were evaluated (expected average FEV1 was 79.5%, the mean baseline nocturnal asthma symptom score for the treatment group was between 1.04-1.18; beclomethasone dipropionate The average baseline dose is 265ug per day, and the dosage range is between 42 and 1008ug per day; the average baseline dose of triamcinolone is 572ug per day, and the dosage range is between 200-1200ug per day).
See Figure 2 for the changes in the asthma symptom scores of patients at 0-12 weeks compared to the baseline period. Compared with the placebo group, the patients receiving the budesonide suspension treatment group had a significant improvement in the nighttime asthma symptom score. Similarly, a similar improvement was observed in the score for daytime asthma symptoms.
Inhaled budesonide suspension 0.5 mg twice daily significantly improved FEV1, and two doses (0.25 mq and 0.5 mg twice daily) significantly increased PEF in the morning compared to placebo.
Patients receiving once-daily or twice-daily dosing < br Budesonide inhalation suspension at 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg daily The efficacy at a single dose was evaluated in 469 pediatric patients 12 months to 8 years old (the average baseline nocturnal asthma symptom score in the treatment group ranged from 1.13-1.31). About 70% of patients have not previously been treated with inhaled corticosteroids. The change of the patient's nocturnal asthma symptom score from baseline at week 0-12 is shown in FIG. 3. Compared to the placebo control group, patients receiving 0.25 mg and 0.5 mg twice daily, and 1 mq once daily doses had significantly improved nighttime asthma symptom scores. Similarly, a similar improvement was observed in the score for daytime asthma symptoms.
Compared with the placebo group, this product can significantly improve FEV1 when administered in two daily doses of 0.5mg, and can be significantly improved in 0.25mg and 0.5mg twice daily and 1mg once daily Patient's morning PEF.
There is evidence to support the efficacy of this product once or twice daily at the same labeled dose. However, when all measurements are considered, the study data are more supportive of the twice-daily dosing regimen (see the Usage and Dosage section).

Pharmacology and toxicology of budesonide suspension for inhalation

This product is not a halogen-containing adrenal corticosteroid. It can inhibit the inflammation of the respiratory tract, reduce the hyperresponsiveness of the respiratory tract, and relieve bronchospasm.
Budesonide is an anti-inflammatory corticosteroid with strong glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide's affinity to the glucocorticoid receptor is about 200 times that of cortisol, and its local anti-inflammatory ability is about 1,000 times that of the latter (rat croton oil-induced ear edema test) . As a result of systemic activity evaluation, in the rat thymus degeneration test of budesonide, the efficacy of subcutaneous administration was about 40 times that of cortisol, and the efficacy of oral administration was about 25 times that of the latter.
The activity of the budesonide suspension for inhalation comes from its active drug budesonide. In the glucocorticoid receptor affinity study, the activity of the 22R configuration is approximately twice that of its epimer 22S configuration. In vitro studies have shown that the two configurations of budesonide do not transform into each other.
The exact mechanism of action of glucocorticoids in asthma inflammation is unknown. Inflammation is an important part of the pathogenesis of asthma. Glucocorticoids have been certified for a variety of cell types (such as mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (such as histamine, eicosanoids, and cytokines) ) Extensive inhibition of allergic or non-allergic inflammation involved. The therapeutic effect of glucocorticoids on asthma may be attributed to its anti-inflammatory effect.
Topical anti-inflammatory in a series of extensively inhaled budesonide formulations for asthma patients in different formulations and drug delivery systems including inhalation drivers, multi-dose dry powder inhalants, nebulized inhalation suspensions and drug delivery systems The activity shows advantages over systemic administration of glucocorticoids. This phenomenon can be explained by the relatively higher local anti-inflammatory effect obtained by local administration, which avoids the significant first-pass degradation effect of the liver (85% -95%) and low-potency metabolites.
Pharmacodynamics < br The therapeutic effect of traditional doses of inhaled budesonide can be largely explained by its local effects on the respiratory tract. In order to confirm that systemic absorption was not a significant influencing factor for the clinical efficacy of inhaled budesonide, a clinical study was performed in adult asthma patients to compare 400ug budesonide administered via a pressurized metered dose inhalation device equipped with a distance tube The effect is different from 1400ug orally and placebo. The study confirmed that although the systemic drug concentration levels of the two formulations were approximately close, there was a therapeutic effect with inhaled budesonide, but oral budesonide did not show clinical efficacy.
Improvements in the control of asthma symptoms after inhalation of budesonide suspension appeared within 2-8 days after the start of treatment, but the maximum treatment benefit of the drug was not reached in the next 4-6 weeks.
A number of stress models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate, have been demonstrated to reduce the bronchial hyperresponsiveness of asthma patients when administered via a dry powder inhaler. However, the relevance of these models to clinical practice is unclear.
Budesonide was administered prophylactically via a dry powder inhaler at a daily dose of 1600ug (800ug twice a day) for 2 weeks, which could reduce the acute allergic reaction (early reaction) and delay of the host after inhaled allergen stimulation. (Late reaction) Decrease in FEV1.
The effects of inhaled budesonide suspension on the HPA functional axis were explored in three, 12-week, double-blind, placebo-controlled clinical trials that were conducted between 6 months and 8 years of age, 293 children with persistent asthma. For most patients, the ability to increase cortisol production did not occur in the stress response evaluated using the short-term tetapeptide corticosteroid (ACTH) stimulation test after treatment with the recommended dose of inhaled budesonide suspension Variety. In a subgroup of children aged 6 months to 2 years (n = 21), patients received total daily doses equivalent to 0.25 mg (n = 5), 0.5 mg (n = 5), and 1 mg (n = 8) After treatment with inhaled budesonide suspension or placebo (n = 3), the average change in ACTH-stimulated cortisol levels at 12 weeks decreased from baseline, compared with placebo Peak cortisol levels increased in the group at 12 weeks. These changes were not statistically significant compared to placebo on average. Another trial was conducted in 141 children aged 6-12 months with mild to moderate asthma or recurrent / essential wheezing. All patients were randomly assigned to receive once-daily 0.5 mg or 1 mg inhaled budesonide suspension, or placebo.
A total of 28, 17, and 31 patients in the 0.5 mg, 1 mg inhaled budesonide suspension, and placebo-treated groups had serum cortisol levels after ACTH stimulation at the baseline and end of the study, respectively. evaluation of. Patients treated with inhaled budesonide suspension compared to the placebo group, the mean change in cortisol from ACTH stimulation at 12 weeks after deduction of baseline plasma cortisol levels did not show adrenal suppression . However, 7 patients in this trial (4 of whom received 0.5 mg of this product, 2 received 1 mg of this product, and 1 received a placebo) showed normal baseline stimulating cortisol levels at week 12 ( 500nmol / L) towards a lower than normal level ([500nmol / L). In four of these patients treated with inhaled budesonide suspension, cortisol levels were close to a cut-off value of 500 nmol / L.
Inhaled budesonide suspension 0.5 mg twice daily, and inhaled budesonide suspension 1 mg and 2 mg twice daily (respectively twice the clinically recommended daily maximum daily dose The effect on 24-hour urinary cortisol excretion was studied in 18 children with persistent asthma aged 6-15 years using a crossover trial design (4 weeks of treatment at each dose level). Dosing at 2 and 4 times the clinically recommended daily dose can result in a dose-dependent decrease in the amount of cortisol excretion in urine. These two higher doses of inhaled budesonide suspension (1 mg and 2 mg, twice daily) significantly reduced (43-52%) the amount of cortisol in urine compared to the study introduction period. excretion. The highest recommended dose of budesonide suspension for inhalation, which is a total daily dose of 1 mg, has not been shown to significantly reduce the excretion of cortisol in urine compared to the level during introduction.

Pharmacokinetics of budesonide suspension for inhalation

absorb:
In children with asthma aged 4-6 years, the absolute bioavailability (eg, lung + oral cavity) of whole body given by inhaled budesonide suspension (eg, lung + oral cavity) is about 6% of the indicated dose.
In children, a peak plasma concentration of 2.6 nmol / L can be reached after about 20 minutes of 1 mg drug nebulization. As assessed by AUC and Cmax, children and adults had the same systemic exposure after absorbing the same dose of inhaled budesonide suspension.
Distribution :
In 4-6 year old children with asthma, budesonide has a steady-state plasma volume of 3L / kg, which is the same as that of healthy adults. Budesonide's plasma protein binding rate is 85% -90%. When the recommended dosage is reached or exceeded, the plasma protein binding degree of the drug is constant within the blood concentration range of 1-100 nmol / L. Budesonide hardly binds to corticosteroid-binding globulin. Budesonide quickly binds to red blood cells and reaches equilibrium. This process is independent of drug concentration, and the whole blood / plasma concentration ratio is about 0.8.
Metabolism :
In vitro studies using human liver homogenates have shown that budesonide is rapidly and fully metabolized in the body. The two main metabolites for biotransformation catalyzed by cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) are 16a-hydroxyprednisolone and 6b-hydroxybudesonide. The glucocorticoid activity of both metabolites is less than 1% of the parent compound. No difference was found between in vivo and in vitro metabolic forms. The negligible metabolic inactivation observed in human lung and serum products.
Excretion and elimination :
Budesonide is mainly cleared by the liver, and metabolites are excreted by urine and feces. In adults, about 60% of the radiolabeled dose is excreted in the urine after intravenous administration. No prototype drug was detected in urine.
Among children with asthma aged 4-6 years, the terminal half-life after aerosol administration of budesonide was 2.3 hours, and the systemic clearance was 0.5L / min. After correction for weight difference, it was increased by about 50% compared with healthy adults .
Special population :
Pharmacokinetics do not vary by race, gender or age.
Liver insufficiency :
Hepatic insufficiency may affect the elimination of corticosteroids. Doubled systemic bioavailability after oral administration proves that pharmacokinetics of budesonide is affected by liver damage. However, the intravenous pharmacokinetics of budesonide are similar to those in healthy adult subjects in patients with cirrhosis.
Breastfeeding women :
Eight lactating women with asthma, 200 or 400 ug per day, twice a day, inhaled budesonide suspension for 3 months, and studied 1-6 months postpartum. Budesonide's systemic exposure in these women was similar to that of non-lactating asthma women in other studies. Analysis of breast milk at 8 hours after dosing showed that the maximum drug concentrations in milk after administration of 400 and 800 ug budesonide were 0.39 and 0.78 nmol / L, respectively, within 45 minutes after dosing.
Infants are expected to orally absorb budesonide from breast milk through the two dosing regimens used in this study. The daily doses of budesonide are approximately 0.007 and 0.014ug / kg / day, respectively, accounting for approximately 0.3% of the mother's inhaled drug dose %. Budesonide plasma levels detected from plasma samples obtained at 90 minutes (and approximately 140 minutes after mother's administration) of 5 infants were below the limit of quantification (4 infants <0.02 nmol / L, and 1 infant <0.04nmol / L) (see [Precautions], [Medication for pregnant and lactating women]).

Budesonide suspension for inhalation

Store at 8-30 ° C. Do not refrigerate.

Budesonide suspension packaging for inhalation

The budesonide suspension for inhalation is contained in a single-dose polyethylene bottle.
5 pcs / box, 30 pcs / box.

Expiration date of budesonide suspension for inhalation

24 months

Standard for inhalation of budesonide suspension

Import drug registration standard JX20090902 ^[1]