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What is this medicine?
FLUTICASONE; SALMETEROL inhalation is for treating asthma that is not controlled with other asthma medicines or when more than one treatment is necessary. Fluticasone is a corticosteroid which decreases inflammation in the lungs. Salmeterol helps open the airways in the lungs. This medicine is intended for regular use. It will not cure your condition, but when used regularly it can open up your air passages and make breathing easier. It will not relieve an acute asthma attack. Fluticasone; salmeterol can be used along with other inhaled or oral asthma medications.
What should I tell my health care provider before I take this medicine?
They need to know if you have any of these conditions:
an asthmatic attack or bronchospasm
chicken pox or measles (recent exposure or infection)
diabetes
heart disease including high blood pressure, irregular heart beat, blockage in heart vessels
immune system problems
infection, especially fungal infection or tuberculosis
liver disease
osteoporosis or other bone disease
overactive thyroid
pheochromocytoma
seizures
an unusual or allergic reaction to Fluticasone, Salmeterol, other corticosteroids, other medicines, foods, dyes, or preservatives
pregnant or trying to get pregnant
breast-feeding
How should this medicine be used?
DO NOT use this medicine for an asthma attack. If you have severe onset or worsening of cough, wheezing, chest tightness, and/or shortness of breath seek immediate medical attention. Always keep a short-acting asthma medication such as albuterol on hand for asthma attacks.
This medicine is for inhalation through the mouth. Shake the inhaler well for 5 seconds before each spray. Prime the inhaler before the first use with 4 test sprays pointing away from your face. If you drop the inhaler or of it has not been used for 4 weeks, prime it with 2 test sprays pointing away from your face. Avoid contact with eyes. After using the inhaler, rinse your mouth with water to minimize build-up of medicine; do not swallow the water. Clean your inhaler at least once a week. Never place the inhaler in water to determine how much medicine is in it. Do not use more than the recommended dose.
Contact your pediatrician or health care professional regarding the use of this medicine in children. Special care may be needed.
NOTE: This medicine is only for you. Don’t share it with others.
What if I miss a dose?
If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, take only that dose and continue with your regular schedule, spacing doses evenly. Do not use double or extra doses.
What may interact with this medicine?
arsenic trioxide
astemizole
bepridil
beta-blockers, often used for high blood pressure or heart problems
caffeine
certain antibiotics (such as clarithromycin, erythromycin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, linezolid, moxifloxacin, sparfloxacin)
chloroquine
cisapride
droperidol
halofantrine
levomethadyl
medicines for colds and breathing difficulties
medicines for heart disease or high blood pressure
medicines known as MAO inhibitors, such as phenelzine (Nardil®), tranylcypromine (Parnate®), isocarboxazid (Marplan®), and selegiline (Carbex®, Eldepryl®)
medicines to control heart rhythm (examples: amiodarone, disopyramide, dofetilide, flecainide, procainamide, quinidine, sotalol)
medicines for treating depression or mental illness (amoxapine, haloperidol, maprotiline, pimozide, phenothiazines, risperidone, sertindole, tricyclic antidepressants, ziprasidone)
methadone
pentamidine
probucol
some medicines for weight loss (including some herbal products, ephedra, ephedrine, dextroamphetamine)
steroid hormones such as dexamethasone, cortisone, hydrocortisone
terfenadine
theophylline
thyroid hormones
water pills or diuretics
Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.
What should I watch for while taking this medicine?
Visit your prescriber or health care professional for regular checks on your progress. Carry an identification card with your name, the type and dose of medicine you are taking, and your prescriber’s name and address. It can take up to 2 weeks before you see the full effect of this medicine.
Check with your prescriber or health care professional if your symptoms do not improve. Seek emergency medical attention if your breathing problems get worse quickly while taking this medicine, or if your rescue inhaler (like albuterol) does not help your breathing. If you find that you are using your rescue inhaler more than normal or it is not as effective in treating your symptoms, you should contact your health care professional as soon as possible. You may need a change of therapy or may be having worsening of your lung condition. Do not stop using this medicine except on your prescriber’s advice.
Using your inhalers regularly as prescribed will help control your symptoms; try not to run out of your medications. It is recommended that you keep an extra refill of your inhalers on hand in case you need them.
Tell your prescriber or health care professional if you are exposed to anyone with measles or chickenpox, or if you develop sores or blisters that do not heal properly.
People who are taking certain dosages of this medicine may need to avoid getting certain vaccines or may need to have changes in their vaccination schedules to ensure adequate protection from certain diseases. Make sure to tell your prescriber or health care professional that you are taking fluticasone; salmeterol before receiving any vaccine.
If you are going to have surgery tell your prescriber or health care professional that you are using this medicine.
What side effects may I notice from this medicine?
Side effects that you should report to your prescriber or health care professional as soon as possible:
chest pain
dizziness or lightheadedness
fever or chills
skin rash and itching (hives)
sore mouth with white patches in the mouth or throat
troubled breathing or wheezing
unusual swelling
unusual tiredness or weakness
vision problems
vomiting
Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
coughing, hoarseness, throat irritation
diarrhea
headache
nausea
nervousness
sore throat
stomach upset
stuffy nose
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15—30 degrees C (59—86 degrees F) with mouthpiece facing down. Keep away from heat or open flames.
Uses
This product is used to control and prevent symptoms (wheezing and shortness of breath) caused by asthma or ongoing lung disease (chronic obstructive pulmonary disease-COPD, which includes chronic bronchitis and emphysema). It contains 2 medications: fluticasone and salmeterol. Fluticasone belongs to a class of drugs known as corticosteroids. It works by reducing the irritation and swelling of the airways. Salmeterol belongs to the class of drugs known as long-acting beta agonists. It works by opening airways in the lungs to make breathing easier. Controlling symptoms of breathing problems can decrease time lost from work or school.
When used alone, long-acting beta agonists (such as salmeterol) may rarely increase the risk of serious (sometimes fatal) asthma-related breathing problems. However, combination inhaled corticosteroid and long-acting beta agonists, such as this product, do not increase the risk of serious asthma-related breathing problems. For asthma treatment, this product should be used when breathing problems are not well controlled with one asthma-control medication (such as inhaled corticosteroid) or if your symptoms need combination treatment.
Before using this medication, it is important to learn how to use it properly. This medication must be used regularly to be effective. It does not work right away and should not be used to relieve sudden asthma attacks. If an asthma attack occurs, use your quick-relief inhaler (such as albuterol, also called salbutamol in some countries) as prescribed.
How to use Advair Diskus Blister, With Inhalation Device
Read the Patient Information Leaflet and Instructions for Use provided by your pharmacist before you start using this medication and each time you get a refill. Follow the illustrated directions for the proper use of this medication. If you have any questions, ask your doctor or pharmacist.
Use this device in a level, flat position. Inhale this medication by mouth as directed by your doctor, usually twice daily (in the morning and evening, 12 hours apart). You may or may not taste/feel the drug when you inhale. Either is normal. Do not exhale into the device.
Do not take the inhaler apart or wash the mouthpiece or any part of the device. Close the device after each use.
If you are using other inhalers at the same time, wait at least 1 minute between the use of each medication, and use this drug last.
Gargle and rinse your mouth with water after each use of this medication to help prevent irritation and yeast infections (thrush) in the mouth and throat. Do not swallow the rinse water.
The dosage is based on your medical condition, age, and response to treatment.
Use this medication regularly in order to get the most benefit from it. This medication works best if used at evenly spaced times. To help you remember, use it at the same times each day. Do not increase your dose, use this medication more often, or stop using it without talking with your doctor. Also, do not use other long-acting beta agonists while using this medication.
If you have been using a quick-relief inhaler (such as albuterol, also called salbutamol in some countries) on a regular daily schedule (such as 4 times daily), you must stop this schedule and only use the quick-relief inhaler as needed for sudden shortness of breath/asthma attacks. Consult your doctor for details.
If you are regularly using a different corticosteroid taken by mouth (such as prednisone), you should not stop using it unless directed by your doctor. You may have withdrawal symptoms if the drug is suddenly stopped. Some conditions (such as asthma, allergies) may become worse when the drug is suddenly stopped. To prevent withdrawal symptoms (such as weakness, weight loss, nausea, muscle pain, headache, tiredness, dizziness), your doctor may direct you to slowly lower the dose of your old medication after you begin using this product. Consult your doctor or pharmacist for more details, and report any withdrawal reactions right away. See also Precautions section.
It may take 1 week or longer before you get the full benefit of this drug. Tell your doctor if your condition does not improve or if it worsens.
Learn which of your inhalers you should use every day (controller drugs) and which you should use if your breathing suddenly worsens (quick-relief drugs). Ask your doctor ahead of time what you should do if you have new or worsening cough or shortness of breath, wheezing, increased sputum, worsening peak flow meter readings, waking up at night with trouble breathing, if you use your quick-relief inhaler more often (more than 2 days a week), or if your quick-relief inhaler does not seem to be working well. Learn when you can treat sudden breathing problems by yourself and when you must get medical help right away.
Side Effects
Hoarseness, throat irritation, headache, or stomach upset may occur. If any of these effects persist or worsen, tell your doctor promptly.
This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high.
Infrequently, this medication may cause severe sudden worsening of breathing problems/asthma immediately after use. If you have sudden worsening of breathing, use your quick-relief inhaler and get medical help right away.
Tell your doctor right away if any of these unlikely but serious side effects occur: white patches on tongue/in mouth, signs of infection (such as fever, persistent sore throat), mental/mood changes (such as nervousness), trouble sleeping, vision problems (such as blurred vision), increased thirst/urination, muscle cramps, shaking (tremors).
Get medical help right away if any of these rare but seriouschest pain, fast/irregular heartbeat, severe dizziness, fainting, seizures.
A very serious allergic reaction to this product is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
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LMICORT dry powder inhaler with an incidence of ≥ 1% in the budesonide group and were more common than in the placebo group:
1-3%: neck pain , syncope , abdominal pain , dry mouth, vomiting, weight gain, fracture, myalgia , hypertonia , migraine , ecchymosis , insomnia , infection, taste perversion, voice alteration.
dyspepsia , gastroenteritis, nausea, and back pain, compared with doses of 400 mcg twice daily.
usitis, headache, oral candidiasis, pain, asthenia , dyspepsia, arthralgia , cough increased, nausea and rhinitis .
: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema , bronchospasm, rash , contact dermatitis , urticaria , and cough, wheezing or bronchospasm in patients with severe milk protein hypersensitivity [see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS ]
: symptoms of hypocorticism and hypercorticism [see WARNINGS AND PRECAUTIONS ]
: cataracts, glaucoma, increased intraocular pressure [see WARNINGS AND PRECAUTIONS ]
: psychiatric symptoms including psychosis , depression , aggressive reactions, irritability, nervousness, restlessness, and anxiety
: throat irritation
: skin bruising
metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER (budesonide inhalation powder) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin , indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS and PRECAUTIONS ]. & Precautions
PRECAUTIONS section.
pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER. When such an infection develops, it should be treated with appropriate local or systemic (i.e. oral antifungal ) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be interrupted. Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.
shortness of breath . When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g. albuterol ) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER (budesonide inhalation powder) .
contact dermatitis , urticaria , angioedema , and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see CONTRAINDICATIONS and ADVERSE REACTIONS ].
lactose , which contains trace levels of milk proteins. It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy . [see CONTRAINDICATIONS and ADVERSE REACTIONS , Post-marketing Experience ].
immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information .) If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.
leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with non-corticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or ocular simplex.
pituitary -adrenal (HPA) function.
prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.
trauma , surgery, or infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT FLEXHALER (budesonide inhalation powder) may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
is during therapy with PULMICORT FLEXHALER (budesonide inhalation powder) . Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [ PEF ]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude , weakness, nausea and vomiting, and hypotension .
rhinitis , conjunctivitis , eczema , arthritis , eosinophilic conditions). Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression ) despite maintenance or even improvement of respiratory function.
nction than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of PULMICORT FLEXHALER (budesonide inhalation powder) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose . Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT FLEXHALER (budesonide inhalation powder) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
budesonide may occur [see DRUG INTERACTIONS , CLINICAL PHARMACOLOGY ].
bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis , post menopausal status, tobacco use, advance age, poor nutrition , or chronic use of drugs that can reduce bone mass (e.g, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.
DOSAGE AND ADMINISTRATION , Use in Specific Populations ].
ased intraocular pressure , and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.
vasculitis consistent with Churg-Strauss syndrome , a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia , vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.
FDA Approved Patient Labeling .
Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while still continuing therapy with PULMICORT FLEXHALER (budesonide inhalation powder) , but at times therapy with PULMICORT FLEXHALER (budesonide inhalation powder) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised. [see WARNINGS AND PRECAUTIONS ] or more inhalations than usual of inhaled, short-acting beta2-agonists
WARNINGS AND PRECAUTIONS ]
CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS ].
CONTRAINDICATIONS ].
immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS ]
curred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER (budesonide inhalation powder) [see WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
WARNINGS AND PRECAUTIONS ].
sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER (budesonide inhalation powder) . This lack of sensation does not mean that they did not get the medication. They should not repeat their inhalation even if they did not feel the medication when inhaling [see PATIENT INFORMATION ].
² basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.1 and 0.2 times, respectively, the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, on a mcg/m² basis) and in female rats at oral doses up to 50 mc/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age, respectively, on a mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.3 times the maximum recommended daily inhalation doses in adults and children 6 to 17 years of age on a mcg/m² basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.
carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (approximately 0.6 and 0.7 times, respectively the maximum recommended daily inhalation dose in adults and children 6 to 17 years of age on a mcg/m² basis).
Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture.
² basis).
² basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (approximately 0.03 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). : Pregnancy Category B
prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period ), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).
fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT FLEXHALER (budesonide inhalation powder) should be used during pregnancy only if clearly needed.
² basis and at a subcutaneous dose inrats that was approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis.
physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
CLINICAL PHARMACOLOGY , Pharmacokinetics, Special Populations, Nursing Mothers ]. No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar. PULMICORT FLEXHALER (budesonide inhalation powder) should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant. Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER (budesonide inhalation powder) immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure. However, in general, PULMICORT FLEXHALER (budesonide inhalation powder) use should not delay or interfere with infant feeding.
Clinical Studies ]. Efficacy results in this age group were similar to those observed in patients 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.
laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids including the impact on final adult height are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
puberty during the course of the study.
metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of inhaled budesonide on growth is not fully known.
FLEXHALER (budesonide inhalation powder) , should be monitored (eg, via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT FLEXHALER (budesonide inhalation powder) , each patient should be titrated to the lowest dose that effectively controls his/her asthma [see DOSAGE AND ADMINISTRATION ].
closely monitored. & Contraindications
WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression ]. Another budesonide-containing dry powder inhaler at 3200 mcg daily administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.
² basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 380 times the maximum recommended daily inhalation dose in adults and approximately 450 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m² basis) and less than 100 mg/kg in rats (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age based on a mcg/m² basis).
asymptomatic . The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism. WARNINGS AND PRECAUTIONS , DESCRIPTION ].
corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus assay. The clinical significance of this is unknown.
pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine , eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
below ).
adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.
1 following inhaled allergen challenge.
: The effects of inhaled budesonide on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with inhaled budesonide treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg of inhaled budesonide twice daily for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient taking doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol < 14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label, long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of inhaled budesonide when administered at doses ranging from 100 to 800 mcg twice daily. In patients who had previously been oral steroid -dependent, use of inhaled budesonide at doses ranging from 100 to 800 mcg twice daily was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy.
ved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method and using a different budesonide containing dry-powder inhaler) with an absolute systemic availability of 39% of the metered dose. Peak steady-state plasma concentrations of budesonide delivered from PULMICORT FLEXHALER in adults with asthma (n=39) occurred at approximately 10 minutes post-dose and averaged 0.6 and 1.6 nmol/L at doses of 180 mcg once daily and 360 mcg twice daily, respectively.
red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.
α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations.
postpartum . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations , Nursing Mothers ].
: Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS ].
: At recommended doses, cimetidine , a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.
teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg (approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m² basis).
udy 2 evaluated PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 2 inhalations once daily or 4 inhalations twice daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations twice daily, and placebo in pediatric patients aged 6 to 17 years with mild to moderate asthma. Both of the studies had a 2-week placebo treatment run-in period followed by a 12-week randomized treatment period. The primary endpoint was the difference between baseline and the mean of the treatment-period FEV 1 (adults) or FEV 1 % predicted (children). ≥ 18 years of age and older (Study 1)
≥ 18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV 1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids. Mean change from baseline in FEV 1 in the PULMICORT FLEXHALER (budesonide inhalation powder) 180 mcg, 2 inhalations twice-daily group was 0.28 liters, as compared to 0.10 liters in the placebo group (p < 0.001). Secondary endpoints of morning and evening peak expiratory flow rate, daytime asthma symptom severity, nighttime asthma symptom severity, daily rescue medication use, and the percentage of patients who met predefined asthma related withdrawal criteria showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 1 (L) otnote : PULMICORT TURBUHALER; a different PULMICORT DPI Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.
1 84.9%). The study population included patients previously treated with inhaled corticosteroids for no more than 30 days before the study began (4%) and patients who were naïve to inhaled corticosteroids (96%). Mean change from baseline in % predicted FEV 1 during the 12-week treatment period in the PULMICORT FLEXHALER (budesonide inhalation powder) 90 mcg, 4 inhalations twice daily treatment group was 5.6 compared with 0.2 in the placebo group (p < 0.001). Secondary endpoints of morning and evening PEF showed differences from baseline favoring PULMICORT FLEXHALER (budesonide inhalation powder) over placebo (p < 0.001). 1

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Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList

<h1>Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList</h1>

Pulmicort Respules (Budesonide Inhalation Suspension) – updated on RxList

Skin and subcutaneous tissue disorders contact dermatitis , eczema , pustular rash, pruritus ,
The incidence of reported adverse events was similar between the 447 PULMICORT RESPULES-treated (mean total daily dose 0.5 to 1 mg) a
Endocrine disorders : symptoms of hypocorticism and hypercorticism [see WARNINGS AND PRECAUTIONS
Eye disorders : cataracts, glaucoma, increased intraocular pressure [see WARNINGS AND PRECAUTIONS
General disorders and administration site conditions fever ,
Immune system disorders : immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema , bronchospasm, rash, contact dermatitis , and urticaria [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS
Infection and Infestation sinusitis , pharyngitis ,
Musculoskeletal and connective tissue disorders avascular necrosis of the femoral head, osteoporosis
Nervous system disorders :
Psychiatric disorders : psychiatric symptoms including psychosis , depression , aggressive reactions, irritability, nervousness, restlessness, and
Respiratory, thoracic, and mediastinal disorders cough
Skin and subcutaneous tissue disorders :
Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS and Use In Specific Populations , Pediatric Use Inhibitors of Cytoch
The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of PULMICORT RESPULES (budesonide inhalation suspension) with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin , indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY , Pharmacokinetics Warnings &
Included as part of the PRECAUTIONS
In clinical trials with PULMICORT RESPULES (budesonide inhalation suspension) , localized infections with Candida albicans occurred in the mouth and pharynx in some patients. The incidences of localized infections of Candida albicans were similar between the placebo and PULMICORT RESPULES (budesonide inhalation suspension) treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal
Hypersensitivity reactions including anaphylaxis, rash , contact dermatitis , urticaria , angioedema , and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see CONTRAINDICATIONS
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled immunoglobulin ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information .) If chicken pox develops, treatment with antiviral
The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied. However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with PULMICORT RESPULES (budesonide inhalation suspension) . An open-label non-randomized clinical study examined the immune responsiveness of varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with PULMICORT RESPULES (budesonide inhalation suspension) 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (ie, beta2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥ 5.0 (gpELISA value) in response to the vaccination
Inhaled corticosteroids should be used with caution, if at all, in patients with active or tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular
Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic- pituitary -adrenal (HPA)- axis
Patients who have been previously maintained on 20 mg or more per day of prednisone
During this period of HPA-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma , surgery, infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT RESPULES (budesonide inhalation suspension) may provide control of asthma symptoms duri
During periods of stress
Lung function (FEV 1 or PEF ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude , weakness, nausea and vomiting, and hypotension
Transfer of patients from systemic corticosteroid therapy to PULMICORT RESPULES (budesonide inhalation suspension) may unmask allergic or other immunologic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis , conjunctivitis , eosinophilic conditions, eczema, and arthritis [see DOSAGE AND ADMINISTRATION
During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or pain , lassitude, depression
PULMICORT RESPULES (budesonide inhalation suspension) , will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT RESPULES (budesonide inhalation suspension) . Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT RESPULES (budesonide inhalation suspension) should be observed carefully for any e
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis , poor nutrition
Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving PULMICORT RESPULES (budesonide inhalation suspension) routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , each patient should be titrated to his/her lowest effective dose [see Use In Specific Populations, Pediatric Use
Glaucoma, increased intraocular pressure
As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing
In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg- Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia , vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship betw
Caution should be exercised when considering the coadministration of PULMICORT RESPULES with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY , Clinical Pharmacokinetics
Patients should be advised that PULMICORT RESPULES (budesonide inhalation suspension) should be administered with a jet nebulizer connected to a compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of PULMICORT RESPULES (budesonide inhalation suspension) and, therefore, are not recommended. The effects of mixing PULMICORT RESPULES (budesonide inhalation suspension) with other nebulizable medications have not been adequately assessed. PULMICORT RESPULES (budesonide inhalation suspension) should be administered separately in the nebulizer [see DOSAGE AND ADMINISTRATION
Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e. oral) antifungal therapy while still continuing therapy with PULMICORT RESPULES (budesonide inhalation suspension) , but at times therapy with PULMICORT RESPULES (budesonide inhalation suspension) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see WARNINGS AND PRECAUTIONS
PULMICORT RESPULES (budesonide inhalation suspension) is not meant to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2- agonist such as albuterol
Patients should not stop therapy with PULMICORT RESPULES (budesonide inhalation suspension) without physician/provider guidance since symptoms may recur after discontinuation [see WARNINGS AND PRECAUTIONS
Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT RESPULES. Discontinue PULMICORT RESPULES if such reactions occur [see CONTRAINDICATIONS ; WARNINGS AND PRECAUTIONS
Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. If exposure to such a person occurs, and the child has not had chicken pox or been properly vaccinated, a physician should be consulted without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see WARNINGS AND PRECAUTIONS
Patients should be advised that PULMICORT RESPULES (budesonide inhalation suspension) may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to PULMICORT RESPULES (budesonide inhalation suspension) [see WARNINGS AND PRECAUTIONS
Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk [see WARNINGS AND PRECAUTIONS
Patients should be informed that orally inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , may cause a reduction in growth velocity when administered to pediatric patients. Healthcare professionals should closely follow the growth of children and adolescents taking corticosteroids by any route [see WARNINGS AND PRECAUTIONS
Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered [see WARNINGS AND PRECAUTIONS
See accompanying PATIENT INFORMATION
In a two-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.06 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.4 and 0.1 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m² basis). The concurrent reference corticosteroids ( prednisolone and triamcinolone
In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.8 and 0.2 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mcg/m²
Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked lethal test in Drosophila melanogaster , and DNA repair
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg approximately 0.6 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above approximately 0.2 times than the maximum recommended daily inhalation dose in adults on a mcg/m² basis. No such effects were noted at 5 mcg/kg (approximately 0.04 times the maximum recommended daily inhalation dose in adults on a mcg/m²
– Studies of pregnant women, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (ie, Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period
These s
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis and at subcutaneous dose that was approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis. In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m²
Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic , doses suggests that rodents are more prone Nursing
Budesonide, like other corticosteroids, is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see CLINICAL PHARMACOLOGY , Pharmacokinetics, and Use In Specific Populations, Nursing Mothers
Safety and effectiveness in children six months to 12 months of age has been evaluated but not established. Safety and effectiveness in children 12 months to 8 years of age have been established [see CLINICAL PHARMACOLOGY , Pharmacodynamics, and ADVERSE REACTIONS , Clinical Trials Experience
A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent /persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMICORT RESPULES (budesonide inhalation suspension) or placebo once daily. Adrenal-axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received PULMICORT RESPULES versus placebo. However, on an individual basis, 7 patients in this study (6 in the PULMICORT RESPULES (budesonide inhalation suspension) treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at Week 12 [see CLINICAL PHARMACOLOGY , Pharmacodynamics ]. Pneumonia
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up”
The growth of pediatric patients receiving inhaled corticosteroids, including PULMICORT RESPULES (budesonide inhalation suspension) , should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT RESPULES, each patient should be titrated to his/her lowest effective dose [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS Overdosage &
The potential for acute toxic effects following overdose of PULMICORT RESPULES (budesonide inhalation suspension) is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [see WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression
In mice, the minimal lethal inhalation dose was 100 mg/kg (approximately 410 and 120 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 and 160 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In mice, the minimal oral lethal dose was 200 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults or and children 12 months to 8 years of age on a mg/m² Hypersensitivity to budesonide or any of the ingredients of PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS , DESCRIPTION and ADVERSE REACTIONS , Post-marketing Experience CLINICAL PHARMACOLOGY Mechanism of Action
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol thymus assay. The clinical significance of these findings is unknown.
The activity of PULMICORT RESPULES is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.
The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., , eicosanoids, leukotrienes, and cytokines) involved in allergic- and non-allergic-mediated inflammation. The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activities and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including an inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local antiinflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%) and the low potency of metabolites (see ). Pharmacodynamics
The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally administered budesonide, even though systemic budesonide exposure was comparable for both treatments, indicating that the inhaled treatment is working locally in the lung. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.
reatment, although maximum benefit may not be achieved for 4-6 weeks.
Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and monophosphate) to decrease bronchial hyperresponsiveness in asthmatic patients. The clinical relevance of these models is not certain.
Pre-treatment with budesonide administered as 1600 mcg daily (800 mcg twice daily) via a dry powder inhaler for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV 1 following inhaled challenge. HPA Axis Effects
The effects of PULMICORT RESPULES (budesonide inhalation suspension) on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 pediatric patients, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with PULMICORT RESPULES (budesonide inhalation suspension) treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n=21) receiving a total daily dose of PULMICORT RESPULES equivalent to 0.25 mg (n=5), 0.5 mg (n=5), 1 mg (n=8), or placebo (n=3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of PULMICORT RESPULES (budesonide inhalation suspension) or placebo once daily. A total of 28, 17, and 31 patients in the PULMICORT RESPULES (budesonide inhalation suspension) 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to Week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with PULMICORT RESPULES versus placebo. However, 7 patients in this study (4 of whom received PULMICORT RESPULES (budesonide inhalation suspension) 0.5 mg, 2 of whom received PULMICORT RESPULES (budesonide inhalation suspension) 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level ( ≥ 500 nmol/L) to a subnormal level ( 500 nmol/L) at Week 12. In 4 of these patients receiving PULMICORT RESPULES (budesonide inhalation suspension) , the cortisol values were near the cutoff value of 500 nmol/L.
tatistically significantly reduced urinary cortisol excretion compared to the run-in period.
PULMICORT RESPULES (budesonide inhalation suspension) , like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see WARNINGS AND ]. Pharmacokinetics Absorption
In asthmatic children 4-6 years of age, the total absolute bioavailability (ie, lung + oral) following administration of PULMICORT RESPULES (budesonide inhalation suspension) via jet nebulizer was approximately 6% of the labeled dose.
In children, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization of a 1 mg dose. Systemic exposure, as measured by AUC and Cmax, is similar for young children and adults after inhalation of the same dose of PULMICORT RESPULES (budesonide inhalation suspension) . Distribution
In asthmatic children 4-6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85-90% bound to plasma proteins, the degree of binding being constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism
In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative difference between the and in vivo metabolic patterns has been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination
Budesonide is primarily cleared by the liver. Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.
In asthmatic children 4-6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight. Special Populations
No differences in pharmacokinetics due to race, gender, or age have been identified. Hepatic Insufficiency
Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults. Nursing Mothers
The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum . Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breast-feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see Use In Specific Populations ]. Drug-Drug Interactions Inhibitors of cytochrome P450 enzymes
Ketoconazole : Ketoconazole, a strong inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide [see WARNINGS AND PRECAUTIONS and ].
Cimetidine : At recommended doses, , a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Animal Toxicology Reproductive Toxicology
As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m² basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m²
Three double-blind, placebo-controlled, parallel group, randomized U.S. clinical trials of 12-weeks duration each were conducted in 1018 pediatric patients, 6 months to 8 years of age, 657 males and 361 females (798 Caucasians, 140 Blacks, 56 Hispanics, 3 Asians, 21 Others) with persistent asthma of varying disease duration (2 to 107 months) and severity. Doses of 0.25 mg, 0.5 mg, and 1 mg administered either once or twice daily were compared to placebo to provide information about appropriate dosing to cover a range of asthma severity. A Pari-LC-Jet Plus Nebulizer (with a face mask or mouthpiece) connected to a Pari Master compressor was used to deliver PULMICORT RESPULES (budesonide inhalation suspension) to patients in the 3 U.S. controlled clinical trials . The co-primary endpoints were nighttime and daytime asthma symptom scores (0-3 scale). Improvements were addressed in terms of the primary efficacy variables of changes from baseline to the double-blind treatment period in nighttime and daytime asthma symptom scores (scale 0-3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization
Results of the 3
Improvements in lung function were associated with PULMICORT RESPULES (budesonide inhalation suspension) in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV 1
Patients Not Receiving Inhaled Corticosteroid Therapy
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg, 0.5 mg, and 1 mg once daily was evaluated in 344 pediatric patients, 12 months to 8 years of age, with mild to moderate persistent asthma (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.07 to 1.34) who were not well controlled by bronchodilators alone. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with PULMICORT RESPULES compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
Changes from baseline to the double-blind phase for the budesonide treatment groups compared to placebo were made using analysis of variance techniques. The model included terms for the respective changes from baseline as the dependent variable and terms for treatment, center and treatment by center interaction as exploratory variables. (See Figures 1-3 ). Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline
Patients Previously Maintained on Inhaled Corticosteroids
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg and 0.5 mg twice daily was evaluated in 133 pediatric asthma patients, 4 to 8 years of age, previously maintained on inhaled corticosteroids (mean FEV 1 79.5% predicted; mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.04 to 1.18; mean baseline dose of beclomethasone dipropionate of 265 mcg/day, ranging between 42 to 1008 mcg/day; mean baseline dose of triamcinolone acetonide of 572 mcg/day, ranging between 200 to 1200 mcg/day). The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with PULMICORT RESPULES (budesonide inhalation suspension) compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
Statistically significant increases in FEV 1 compared to placebo were observed with PULMICORT RESPULES (budesonide inhalation suspension) at a dose of 0.5 mg twice daily and in morning PEF for both doses (0.25 mg and 0.5 mg twice daily). Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline
Patients Receiving Once-Daily or Twice-Daily Dosing
The efficacy of PULMICORT RESPULES (budesonide inhalation suspension) at doses of 0.25 mg once daily, 0.25 mg twice daily, 0.5 mg twice daily, and 1 mg once daily, was evaluated in 469 pediatric patients 12 months to 8 years of age (mean baseline nighttime asthma symptom scores of the treatment groups ranged from 1.13 to 1.31). Approximately 70% were not previously receiving inhaled corticosteroids. The changes from baseline to Weeks 0-12 in nighttime asthma symptom scores are shown in Figure 3. PULMICORT RESPULES at doses of 0.25 mg and 0.5 mg twice daily, and 1 mg once daily, demonstrated statistically significant decreases in nighttime asthma symptom scores compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.
PULMICORT RESPULES (budesonide inhalation suspension) at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV 1 , and at doses of 0.25 mg and 0.5 mg twice daily and 1 mg once daily statistically significant increases in morning PEF.
The evidence supports the efficacy of the same nominal dose of PULMICORT RESPULES (budesonide inhalation suspension) administered on either a once-daily or twice-daily schedule. However, when all measures are considered together, the evidence is stronger for twice-daily dosing (see DOSAGE AND ADMINISTRATION ). Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry. Nighttime Asthma Change from Baseline Medication Guide OVERDOSE
The potential for acute toxic effects following overdose of PULMICORT RESPULES (budesonide inhalation suspension) is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur [see WARNINGS AND PRECAUTIONS , Hypercorticism and Adrenal Suppression
In mice, the minimal lethal inhalation dose was 100 mg/kg (approximately 410 and 120 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 and 160 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In mice, the minimal oral lethal dose was 200 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults and children 12 months to 8 years of age on a mg/m² basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 and 240 times, respectively, the maximum recommended daily inhalation dose in adults or and children 12 months to 8 years of age on a mg/m² Hypersensitivity to budesonide or any of the ingredients of PULMICORT RESPULES [see WARNINGS AND PRECAUTIONS , DESCRIPTION and ADVERSE REACTIONS , Post-marketing Experience

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Pulmicort Turbuhaler (Budesonide) – updated on RxList

<h1>Pulmicort Turbuhaler (Budesonide) – updated on RxList</h1>

Pulmicort Turbuhaler (Budesonide) – updated on RxList

Copyright © 2018 by RxList Inc. RxList does not provide medical advice, diagnosis or treatment. See additional information . Pulmicort Turbuhaler
(budesonide) Inhalation Powder 200 mcg
For Oral Inhalation Only. DESCRIPTION
Budesonide, the active component of PULMICORT TURBUHALER (budesonide) 200 mcg, is a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is:
Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform . Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 10 3 .
PULMICORT TURBUHALER (budesonide) is an inhalation-driven multi-dose dry powder inhaler that contains only micronized budesonide. Each actuation of PULMICORT TURBUHALER provides 200 mcg budesonide per metered dose, which delivers approximately 160 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec).
In vitro testing has shown that the dose delivery for PULMICORT TURBUHALER (budesonide) is substantially dependent on airflow through the device. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use (see Patient’s Instructions for Use ). In adult patients with asthma (mean FEV 1 2.9 L [0.8 – 5.1 L]) mean peak inspiratory flow (PIF) through PULMICORT TURBUHALER (budesonide) was 78 (40-111) L/min. Similar results (mean PIF 82 [43-125] L/min) were obtained in asthmatic children (6 to 15 years, mean FEV 1 2.1 L [0.9 – 5.4 L]). Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery. Indications & Dosage INDICATIONS
PULMICORT TURBUHALER (budesonide) is indicated for the maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older. It is also indicated for patients requiring oral corticosteroid therapy for asthma. Many of those patients may be able to reduce or eliminate their requirement for oral corticosteroids over time.
PULMICORT TURBUHALER (budesonide) is NOT indicated for the relief of acute bronchospasm. DOSAGE AND ADMINISTRATION
PULMICORT TURBUHALER (budesonide) should be administered by the orally inhaled route in asthmatic patients age 6 years and older. Individual patients will experience a variable onset and degree of symptom relief. Generally, PULMICORT TURBUHALER (budesonide) has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhaled administration of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The safety and efficacy of PULMICORT TURBUHALER (budesonide) when administered in excess of recommended doses have not been established.
The recommended starting dose and the highest recommended dose of PULMICORT TURBUHALER (budesonide) , based on prior asthma therapy, are listed in the following table.
200 to 400 mcg twice daily 400 mcg twice daily 200 to 400 mcg twice daily 800 mcg twice daily 400 to 800 mcg twice daily 800 mcg twice daily Oral Corticosteroids The highest recommended dose in children is 400 mcg twice daily
*In patients with mild to moderate asthma who are well controlled on inhaled corticosteroids, dosing with PULMICORT TURBUHALER (budesonide) 200 mcg or 400 mcg once daily may be considered. PULMICORT TURBUHALER (budesonide) can be administered once daily either in the morning or in the evening.
If the once-daily treatment with PULMICORT TURBUHALER (budesonide) does not provide adequate control of asthma symptoms, the total daily dose should be increased and/or administered as a divided dose. Patients Maintained on Chronic Oral Corticosteroids
Initially, PULMICORT TURBUHALER (budesonide) should be used concurrently with the patient’s usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. The next reduction is made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 2.5 mg of prednisone or its equivalent. A slow rate of withdrawal is strongly recommended. During reduction of oral corticosteroids, patients should be carefully monitored for asthma instability, including objective measures of airway function, and for adrenal insufficiency (see WARNINGS ). During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude , and depression , despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with PULMICORT TURBUHALER (budesonide) but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.
NOTE: In all patients it is desirable to titrate to the lowest effective dose once asthma stability is achieved. Directions for Use
Illustrated Patient’s Instructions for Use accompany each package of PULMICORT TURBUHALER (budesonide) .
Patients should be instructed to prime PULMICORT TURBUHALER (budesonide) prior to its initial use, and instructed to inhale deeply and forcefully each time the unit is used. Rinsing the mouth after inhalation is also recommended. HOW SUPPLIED
PULMICORT TURBUHALER (budesonide) consists of a number of assembled plastic details, the main parts being the dosing mechanism, the storage unit for drug substance and the mouthpiece. The inhaler is protected by a white outer tubular cover screwed onto the inhaler. The body of the inhaler is white and the turning grip is brown. The following wording is printed on the grip in raised lettering, “Pulmicort™ 200 mcg”. The TURBUHALER inhaler cannot be refilled and should be discarded when empty.
PULMICORT TURBUHALER (budesonide) is available as 200 mcg/dose, 200 doses (NDC 0186-0915-42) and has a target fill weight of 104 mg.
When there are 20 doses remaining in PULMICORT TURBUHALER (budesonide) , a red mark will appear in the indicator window. If the unit is used beyond the point at which the red mark appears at the bottom of the window, the correct amount of medication may not be obtained. The unit should be discarded.
Store with the cover tightened in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP]. Keep out of the reach of children. All trademarks are the property of the AstraZeneca group of companies. ©AstraZeneca 2001, 2006. Manufactured for: AstraZeneca LP, Wilmington, DE 19850 By: AstraZeneca AB, Sodertalje, Sweden 33020-00. Rev. 10/06. FDA Rev date: 8/20/2007 Side Effects SIDE EFFECTS
The following adverse reactions were reported in patients treated with PULMICORT TURBUHALER (budesonide) .
The incidence of common adverse events is based upon double-blind , placebo-controlled US clinical trials in which 1116 adult and pediatric patients age 6-70 years (472 females and 644 males) were treated with PULMICORT TURBUHALER (budesonide) (200 to 800 mcg twice daily for 12 to 20 weeks) or placebo .
The following table shows the incidence of adverse events in patients previously receiving bronchodilators and/or inhaled corticosteroids in US controlled clinical trials. This population included 232 male and 62 female pediatric patients (age 6 to 17 years) and 332 male and 331 female adult patients (age 18 years and greater). Adverse Events with ≥ 3% Incidence reported by Patients on PULMICORT TURBUHALER (budesonide)
Average Duration of Exposure (days) 59 80 80
The table above includes all events (whether considered drug-related or non-drug-related by the investigators) that occurred at a rate of ≥3% in any one PULMICORT TURBUHALER (budesonide) group and were more common than in the placebo group. In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER (budesonide) patients should be taken into account.
The following other adverse events occurred in these clinical trials using PULMICORT TURBUHALER (budesonide) with an incidence of 1 to 3% and were more common on PULMICORT TURBUHALER (budesonide) than on placebo.
Resistance Mechanisms: infection
Special Senses: taste perversion
In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the effects of PULMICORT TURBUHALER (budesonide) 400 mcg twice daily (N=53) and 800 mcg twice daily (N=53) were compared with placebo (N=53) on the frequency of reported adverse events. Adverse events, whether considered drug-related or non-drug-related by the investigators, reported in more than five patients in the PULMICORT TURBUHALER (budesonide) group and which occurred more frequently with PULMICORT TURBUHALER (budesonide) than placebo are shown below (% PULMICORT TURBUHALER (budesonide) and % placebo). In considering these data, the increased average duration of exposure for PULMICORT TURBUHALER (budesonide) patients (78 days for PULMICORT TURBUHALER (budesonide) vs. 41 days for placebo) should be taken into account.
Body As A Whole: asthenia (9% and 2%) headache (12% and 2%) pain (10% and 2%) Digestive: dyspepsia (8% and 0%)nausea (6% and 0%)oral candidiasis (10% and 0%) Musculoskeletal: arthralgia (6% and 0%) Respiratory: cough increased (6% and 2%) respiratory infection (32% and 13%) rhinitis (6% and 2%) sinusitis (16% and 11%) Patients Receiving PULMICORT TURBUHALER (budesonide) Once Daily
The adverse event profile of once-daily administration of PULMICORT TURBUHALER (budesonide) 200 mcg and 400 mcg, and placebo, was evaluated in 309 adult asthmatic patients in an 18-week study. The study population included both patients previously treated with inhaled corticosteroids, and patients not previously receiving corticosteroid therapy. There was no clinically relevant difference in the pattern of adverse events following once-daily administration of PULMICORT TURBUHALER (budesonide) when compared with twice-daily dosing.
Pediatric Studies: In a 12-week placebo-controlled trial in 404 pediatric patients 6 to 18 years of age previously maintained on inhaled corticosteroids, the frequency of adverse events for each age category (6 to 12 years, 13 to 18 years) was comparable for PULMICORT TURBUHALER (budesonide) (at 100, 200 and 400 mcg twice daily) and placebo. There were no clinically relevant differences in the pattern or severity of adverse events in children compared with those reported in adults.
Adverse Event Reports From Other Sources: Rare adverse events reported in the published literature or from worldwide marketing experience with any formulation of inhaled budesonide include: immediate and delayed hypersensitivity reactions including rash , contact dermatitis , urticaria , angioedema and bronchospasm; symptoms of hypocorticism and hypercorticism; glaucoma , cataracts; psychiatric symptoms including depression , aggressive reactions, irritability, anxiety and psychosis . Drug Interactions DRUG INTERACTIONS
In clinical studies, concurrent administration of budesonide and other drugs commonly used in the treatment of asthma has not resulted in an increased frequency of adverse events. The main route of metabolism of budesonide, as well as other corticosteroids, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole , a potent inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of other known inhibitors of CYP3A4 (eg, itraconazole, clarithromycin , erythromycin , etc.) may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors. Warnings WARNINGS
Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT TURBUHALER (budesonide) because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic- pituitary -adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma , surgery , or infection (particularly gastroenteritis ) or other conditions associated with severe electrolyte loss. Although PULMICORT TURBUHALER (budesonide) may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.
During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT TURBUHALER (budesonide) . Lung function (FEV 1 or AM PEF ), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue , lassitude , weakness, nausea and vomiting, and hypotension .
Transfer of patients from systemic corticosteroid therapy to PULMICORT TURBUHALER (budesonide) may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, eg, rhinitis , conjunctivitis , arthritis , eosinophilic conditions, and eczema (see DOSAGE AND ADMINISTRATION ).
Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles , for example, can have a more serious or even fatal course in susceptible pediatric patients or adults on immunosuppressant doses of corticosteroids. In pediatric or adult patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin ( IG ) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.
PULMICORT TURBUHALER (budesonide) is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma.
As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing , may occur after dosing. If bronchospasm occurs following dosing with PULMICORT TURBUHALER (budesonide) , it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with PULMICORT TURBUHALER (budesonide) should be discontinued and alternate therapy instituted.
Patients should be instructed to contact their physician immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with PULMICORT TURBUHALER (budesonide) . During such episodes, patients may require therapy with oral corticosteroids. Precautions PRECAUTIONS General
During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, eg, joint and/or muscular pain, lassitude, and depression , despite maintenance or even improvement of respiratory function (see DOSAGE AND ADMINISTRATION ).
In responsive patients, PULMICORT TURBUHALER (budesonide) may permit control of asthma symptoms with less suppression of HPA- axis function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active, the beneficial effects of PULMICORT TURBUHALER (budesonide) in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose . Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT TURBUHALER (budesonide) .
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT TURBUHALER (budesonide) should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism, reduced bone mineral density , and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, PULMICORT TURBUHALER (budesonide) should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.
Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. A reduction in growth velocity may occur as a result of inadequate control of asthma or from use of corticosteroids for treatment. The potential effects of prolonged treatment on growth velocity should be weighed against the clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , each patient should be titrated to his/her lowest effective dose (see PRECAUTIONS, Pediatric Use ).
Although patients in clinical trials have received PULMICORT TURBUHALER (budesonide) on a continuous basis for periods of 1 to 2 years, the long-term local and systemic effects of PULMICORT TURBUHALER (budesonide) in human subjects are not completely known. In particular, the effects resulting from chronic use of PULMICORT TURBUHALER (budesonide) on developmental or immunological processes in the mouth, pharynx , trachea , and lung are unknown.
In clinical trials with PULMICORT TURBUHALER (budesonide) , localized infections with Candida albicans occurred in the mouth and pharynx in some patients. These infections may require treatment with appropriate antifungal therapy and/or discontinuance of treatment with PULMICORT TURBUHALER (budesonide) .
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal , bacterial , viral or parasitic infections, or ocular herpes simplex.
Rare instances of glaucoma , increased intraocular pressure , and cataracts have been reported following the inhaled administration of corticosteroids. Information for Patients
Patients being treated with PULMICORT TURBUHALER (budesonide) should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects. For proper use of PULMICORT TURBUHALER (budesonide) and to attain maximum improvement, the patient should read and follow the accompanying Patient’s Instructions for Use carefully. Patients should use PULMICORT TURBUHALER (budesonide) at regular intervals as directed since its effectiveness depends on regular use. The patient should not alter the prescribed dosage unless advised to do so by the physician. Patients should be advised that PULMICORT TURBUHALER (budesonide) is not a bronchodilator and is not intended to treat acute or life-threatening episodes of asthma. Patients should be advised that the effectiveness of PULMICORT TURBUHALER (budesonide) depends on proper use of the device and inhalation-administering technique: 1. PULMICORT TURBUHALER (budesonide) must be in the upright position (mouthpiece on top) during loading in order to provide the correct dose. 2. PULMICORT TURBUHALER (budesonide) must be primed when the unit is used for the very first time. To prime the unit, it must be held in an upright position and the brown grip turned fully to the right, then turned fully to the left until it clicks. Repeat. 3. To load the first dose, the grip must be turned fully to the right and fully to the left until it clicks. 4. After the first dose, it is not necessary to prime the unit. However, it must be loaded in the upright position immediately prior to use as described above. 5. Patients should be advised not to shake the inhaler. Patients should place the mouthpiece between the lips and inhale forcefully and deeply. The powder is then delivered to the lungs . Patients should not exhale through PULMICORT TURBUHALER (budesonide) . Due to the small volume of powder, the patient may not taste or sense the presence of any medication entering the lungs when inhaling from the TURBUHALER inhaler. This lack of sensation does not indicate that the patient is not receiving benefit from PULMICORT TURBUHALER (budesonide) . Patients should be advised that rinsing the mouth with water without swallowing after each dosing may decrease the risk of the development of oral candidiasis . Patients should be instructed that they will receive a new PULMICORT TURBUHALER (budesonide) unit each time they refill their prescription. Patients should be advised to discard the whole device after the labelled number of inhalations has been used. When there are 20 doses remaining in PULMICORT TURBUHALER (budesonide) , a red mark will appear in the indicator window. PULMICORT TURBUHALER (budesonide) should not be used with a spacer. The mouthpiece should not be bitten or chewed. The cover should be replaced securely after each opening. Patients should keep PULMICORT TURBUHALER (budesonide) clean and dry at all times. Patients should be advised that improvement in asthma control following inhalation of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer. If symptoms do not improve in that time frame, or if the condition worsens, the patient should be instructed not to increase the dosage, but to contact the physician. Patients whose systemic corticosteroids have been reduced or withdrawn should be instructed to carry a warning card indicating that they may need supplemental systemic corticosteroids during periods of stress or an asthma attack that does not respond to bronchodilators. Patients should be advised not to stop the use of PULMICORT TURBUHALER (budesonide) abruptly. Patients should be warned to avoid exposure to chicken pox or measles and if they are exposed, to consult their physicians without delay. Long-term use of inhaled corticosteroids, including budesonide, may increase the risk of some eye problems (cataracts or glaucoma). Regular eye examinations should be considered. Women considering the use of PULMICORT TURBUHALER (budesonide) should consult with their physician if they are pregnant or intend to become pregnant, or if they are breast-feeding a baby. Patients considering use of PULMICORT TURBUHALER (budesonide) should consult with their physician if they are allergic to budesonide or any other orally inhaled corticosteroid. Patients should inform their physician of other medications they are taking as PULMICORT TURBUHALER (budesonide) may not be suitable in some circumstances and the physician may wish to use a different medicine. Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.
In a 104-week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in male rats receiving an oral dose of 50 mcg/kg/day (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m 2 basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m 2 basis). In two additional two-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m 2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.
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 (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m 2 basis).
Budesonide was not mutagenic or clastogenic in six different test systems: 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.
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m 2 basis).
At 20 mcg/kg/day (less than the maximum recommended human daily inhalation dose on a mcg/m 2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose in adults on a mcg/m 2 basis). Pregnancy: Teratogenic Effects
Pregnancy Category B: As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits (less than the maximum recommended human daily inhalation dose on a mcg/m 2 basis) and 500 mcg/kg/day in rats (approximately 3 times the maximum recommended human daily inhalation dose on a mcg/m 2 basis).
No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to 250 mcg/kg/day (equivalent to the maximum recommended human daily inhalation dose on a mcg/m 2 basis).
Experience with oral corticosteroids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
Studies of pregnant women, however, have not shown that PULMICORT TURBUHALER (budesonide) increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period ), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared with the general population rate (3.8 % vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).
These same data were utilized in a second study bringing the total to 2,534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).
Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT TURBUHALER (budesonide) should be used during pregnancy only if clearly needed. Nonteratogenic Effects
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers
Corticosteroids are secreted in human milk. Because of the potential for adverse reactions in nursing infants from any corticosteroid, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Actual data for budesonide are lacking. Pediatric Use
Safety and effectiveness of PULMICORT TURBUHALER (budesonide) in pediatric patients below 6 years of age have not been established.
In pediatric asthma patients the frequency of adverse events observed with PULMICORT TURBUHALER (budesonide) was similar between the 6- to 12-year age group (N=172) compared with the 13- to 17-year age group (N=124).
Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids including the impact on final adult height are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
In a study of asthmatic children 5-12 years of age, those treated with PULMICORT TURBUHALER (budesonide) 200 mcg twice daily (n=311) had a 1.1- centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with PULMICORT TURBUHALER (budesonide) and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks and benefits associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including PULMICORT TURBUHALER (budesonide) , each patient should be titrated to his/her lowest effective dose. Geriatric Use
One hundred patients 65 years or older were included in the US and non-US controlled clinical trials of PULMICORT TURBUHALER (budesonide) . There were no differences in the safety and efficacy of the drug compared with those seen in younger patients.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic , renal , or cardiac function, and of concomitant disease or other drug therapy. Overdosage & Contraindications OVERDOSE
The potential for acute toxic effects following overdose of PULMICORT TURBUHALER (budesonide) is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur (see PRECAUTIONS ). PULMICORT TURBUHALER at twice the highest recommended dose (3200 mcg daily) administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.
The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 320 times the maximum recommended daily inhalation dose in adults and approximately 380 times the maximum recommended daily inhalation dose in children on a mcg/m 2 basis). There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 430 times the maximum recommended daily inhalation dose in adults and approximately 510 times the maximum recommended daily inhalation dose in children on a mcg/m 2 basis). The minimal oral lethal dose was 200 mg/kg in mice (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children on a mcg/m 2 basis) and less than 100 mg/kg in rats (approximately 630 times the maximum recommended daily inhalation dose in adults and approximately 750 times the maximum recommended daily inhalation dose in children based on a mcg/m 2 basis).
Post-marketing experience showed that patients experiencing acute overdose of inhaled budesonide commonly remained asymptomatic . The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism. CONTRAINDICATIONS
PULMICORT TURBUHALER (budesonide) is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
Hypersensitivity to budesonide contraindicates the use of PULMICORT TURBUHALER (budesonide) . Clinical Pharmacology CLINICAL PHARMACOLOGY Mechanism of Action
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.
The activity of PULMICORT TURBUHALER is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.
The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine , eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses from PULMICORT TURBUHALER (budesonide) . This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see below). Pharmacokinetics Absorption: After oral administration of budesonide, peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6-13%. In contrast, most of budesonide delivered to the lungs is systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lungs (as assessed by plasma concentration method) with an absolute systemic availability of 39% of the metered dose. Pharmacokinetics of budesonide do not differ significantly in healthy volunteers and asthmatic patients. Peak plasma concentrations of budesonide occurred within 30 minutes of inhalation from PULMICORT TURBUHALER.
In asthmatic patients, budesonide showed a linear increase in AUC and Cmax with increasing dose after both a single dose and repeated dosing from PULMICORT TURBUHALER (budesonide) . Distribution: The volume of distribution of budesonide was approximately 3 L/kg. It was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of PULMICORT TURBUHALER. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Metabolism: In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound. No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion/Elimination: The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 60% of an intravenous radiolabelled dose was recovered in the urine. No unchanged budesonide was detected in the urine. Special Populations: No pharmacokinetic differences have been identified due to race, gender or advanced age. Pediatric: Following intravenous dosing in pediatric patients age 10-14 years, plasma half-life was shorter than in adults (1.5 hours vs. 2.0 hours in adults). In the same population following inhalation of budesonide via a pressurized metered-dose inhaler , absolute systemic availability was similar to that in adults. Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy subjects. Drug-Drug Interactions: Ketoconazole, a potent inhibitor of cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids, increased plasma levels of orally ingested budesonide. At recommended doses, cimetidine had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide. Pharmacodynamics
To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered-dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo . The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.
Generally, PULMICORT TURBUHALER (budesonide) has a relatively rapid onset of action for an inhaled corticosteroid. Improvement in asthma control following inhalation of PULMICORT TURBUHALER (budesonide) can occur within 24 hours of beginning treatment although maximum benefit may not be achieved for 1 to 2 weeks, or longer.
PULMICORT TURBUHALER (budesonide) has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.
Pretreatment with PULMICORT TURBUHALER (budesonide) 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV 1 following inhaled allergen challenge.
The effects of PULMICORT TURBUHALER (budesonide) on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 905 adults and 404 pediatric patients with asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by cosyntropin (ACTH) stimulation test, remained intact with PULMICORT TURBUHALER (budesonide) treatment at recommended doses. For adult patients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%, 2%, 6%, and 13% respectively, had an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography following short-cosyntropin test) as compared with 8% of patients treated with placebo. Similar results were obtained in pediatric patients. In another study in adults, doses of 400, 800 and 1600 mcg budesonide twice daily via PULMICORT TURBUHALER (budesonide) for 6 weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose) resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while 10 mg prednisone resulted in a 35% reduction. In this study, no patient on PULMICORT TURBUHALER (budesonide) at doses of 400 and 800 mcg twice daily met the criterion for an abnormal stimulated cortisol response (peak cortisol <14.5 mcg/dL assessed by liquid chromatography) following ACTH infusion. An open-label , long-term follow-up of 1133 patients for up to 52 weeks confirmed the minimal effect on the HPA axis (both basal and stimulated plasma cortisol) of PULMICORT TURBUHALER (budesonide) when administered at recommended doses. In patients who had previously been oral steroid -dependent, use of PULMICORT TURBUHALER (budesonide) in recommended doses was associated with higher stimulated cortisol response compared with baseline following 1 year of therapy.
The administration of budesonide via PULMICORT TURBUHALER (budesonide) in doses up to 800 mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients. However, the long-term effect of PULMICORT TURBUHALER (budesonide) on growth is not fully known. Clinical Trails
The therapeutic efficacy of PULMICORT TURBUHALER (budesonide) has been evaluated in controlled clinical trials involving more than 1300 patients (6 years and older) with asthma of varying disease duration (20 years) and severity.
Double-blind , parallel, placebo-controlled clinical trials of 12 weeks duration and longer have shown that, compared with placebo, PULMICORT TURBUHALER (budesonide) significantly improved lung function (measured by PEF and FEV 1 ), significantly decreased morning and evening symptoms of asthma, and significantly reduced the need for as-needed inhaled β2- agonist use at doses of 400 mcg to 1600 mcg per day (200 mcg to 800 mcg twice daily) in adults and 400 mcg to 800 mcg per day (200 mcg to 400 mcg twice daily) in pediatric patients 6 years of age and older.
Improved lung function (morning PEF) was observed within 24 hours of initiating treatment in both adult and pediatric patients 6 years of age and older, although maximum benefit was not achieved for 1 to 2 weeks, or longer, after starting treatment. Improved lung function was maintained throughout the 12 weeks of the double-blind portion of the trials. Patients Not Receiving Corticosteroid Therapy
In a 12-week clinical trial in 273 patients with mild to moderate asthma (mean baseline FEV 1 2.27 L) who were not well controlled by bronchodilators alone, PULMICORT TURBUHALER (budesonide) was evaluated at doses of 200 mcg twice daily and 400 mcg twice daily versus placebo. The FEV 1 results from this trial are shown in the figure below. Pulmonary function improved significantly on both doses of PULMICORT TURBUHALER (budesonide) compared with placebo.
A 12-Week Trial in Patients Not on Corticosteroid Therapy Prior to Study Entry
In a 12-month controlled trial in 75 patients not previously receiving corticosteroids, PULMICORT TURBUHALER (budesonide) at 200 mcg twice daily resulted in improved lung function (measured by PEF) and reduced bronchial hyperreactivity compared with placebo. Patients Previously Maintained on Inhaled Corticosteroids
The safety and efficacy of PULMICORT TURBUHALER (budesonide) was also evaluated in adult and pediatric patients (age 6 to 18 years) previously maintained on inhaled corticosteroids (adults: N=473, mean baseline FEV 1 2.04 L, baseline doses of beclomethasone dipropionate 126-1008 mcg/day; pediatrics : N=404, mean baseline FEV 1 2.09 L, baseline doses of beclomethasone dipropionate 126-672 mcg/day or triamcinolone acetonide 300-1800 mcg/day). The FEV 1 results of these two trials, both 12 weeks in duration, are presented in the following figures. Pulmonary function improved significantly with all doses of PULMICORT TURBUHALER (budesonide) compared with placebo in both trials.
Adult Patients Previously Maintained on Inhaled Corticosteroids
Pediatric Patients Age 6 to 18 Years Previously Maintained on Inhaled Corticosteroids Patients Receiving PULMICORT TURBUHALER (budesonide) Once Daily
The efficacy and safety of once-daily administration of PULMICORT TURBUHALER (budesonide) 200 mcg and 400 mcg and placebo were also evaluated in 309 adult asthmatic patients (mean baseline FEV 1 2.7 L) in an 18-week study. Compared with placebo, patients receiving Pulmicort 200 or 400 mcg once daily showed significantly better asthma stability as assessed by PEF and FEV 1 over an initial 6-week treatment period, which was maintained with a 200 mcg daily dose over the subsequent 12 weeks. Although the study population included both patients previously treated with inhaled corticosteroids, as well as patients not previously receiving corticosteroid therapy, the results showed that once-daily dosing was most clearly effective for those patients previously maintained on orally inhaled corticosteroids (see DOSAGE AND ADMINISTRATION ). Patients Previously Maintained on Oral Corticosteroids
In a clinical trial in 159 severe asthmatic patients requiring chronic oral prednisone therapy (mean baseline prednisone dose 19.3 mg/day) PULMICORT TURBUHALER (budesonide) at doses of 400 mcg twice daily and 800 mcg twice daily was compared with placebo over a 20-week period. Approximately two-thirds (68% on 400 mcg twice daily and 64% on 800 mcg twice daily) of PULMICORT TURBUHALER (budesonide) -treated patients were able to achieve sustained (at least 2 weeks) oral corticosteroid cessation (compared with 8% of placebo-treated patients) and improved asthma control. The average oral corticosteroid dose was reduced by 83% on 400 mcg twice daily and 79% on 800 mcg twice daily for PULMICORT TURBUHALER (budesonide) -treated patients vs. 27% for placebo. Additionally, 58 out of 64 patients (91%) who completely eliminated oral corticosteroids during the double-blind phase of the trial remained off oral corticosteroids for an additional 12 months while receiving PULMICORT TURBUHALER (budesonide) . Medication Guide PATIENT INFORMATION
Patient’s Instructions For Use
Please read this leaflet carefully before you start to take your medicine. It provides a summary of information on your medicine. Following these instructions helps to ensure that you are inhaling the medication correctly.
FOR FURTHER INFORMATION ASK YOUR DOCTOR OR PHARMACIST.
WHAT YOU SHOULD KNOW ABOUT PULMICORT TURBUHALER (budesonide)
Your doctor has prescribed PULMICORT TURBUHALER 200 mcg. It contains a medication called budesonide, which is a synthetic corticosteroid . Corticosteroids are natural substances found in the body that help fight inflammation . They are used to treat asthma because they reduce the swelling and irritation in the walls of the small air passages in the lungs and ease breathing problems. When inhaled regularly, corticosteroids also help to prevent attacks of asthma.
PULMICORT TURBUHALER (budesonide) treats the inflammation—the “quiet part” of asthma that you cannot hear, see, or feel. When inflammation is left untreated, your asthma symptoms and attacks can increase. PULMICORT TURBUHALER (budesonide) works to prevent and reduce your asthma symptoms and attacks.
IMPORTANT POINTS TO REMEMBER ABOUT PULMICORT TURBUHALER (budesonide)
MAKE SURE that this medicine is suitable for you (see “BEFORE USING YOUR PULMICORT TURBUHALER (budesonide) ”).
It is important that you inhale each dose as your doctor has advised.
Use your Turbuhaler as directed by your doctor. DO NOT STOP TREATMENT OR REDUCE YOUR DOSE EVEN IF YOU FEEL BETTER, unless told to do so by your doctor.
DO NOT inhale more doses or use your Turbuhaler more often than instructed by your doctor.
This medicine is NOT intended to provide rapid relief of your breathing difficulties during an asthma attack. It must be taken at regular intervals as recommended by your doctor, and not as an emergency measure.
Your doctor may prescribe additional medication (such as bronchodilators) for emergency relief if an acute an asthma attack does not respond to the additional medication, you require more of the additional medication than usual.
If you also use another medicine by inhalation, you should consult your doctor for instructions on when to use it in relation to using your PULMICORT TURBUHALER (budesonide) .
BEFORE USING YOUR PULMICORT TURBUHALER (budesonide)
TELL YOUR DOCTOR BEFORE STARTING TO TAKE THIS MEDICINE IF YOU: are pregnant (or intending to become pregnant), are breast-feeding a baby, are allergic to budesonide or any other orally inhaled corticosteroid, have any infections,

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BI 705564 in Patients With Systemic Lupus Erythematosus (SLE)

<h1>BI 705564 in Patients With Systemic Lupus Erythematosus (SLE)</h1>

BI 705564 in Patients With Systemic Lupus Erythematosus (SLE)

Inclusion Criteria: ≥ 18 years at screening. Diagnosis of systemic lupus erythematosus (SLE) at least 6 months prior to screening according to SLICC 2012 criteria; at least 4 criteria must be documented. Positive test results for anti-nuclear antibody (ANA) (human epithelial cell-2 ANA greater than or equal to [>=] 1:80) and/or anti-dsDNA antibody at the Screening visit. To be performed by Central Laboratory. At screening visit a “clinical” Systemic Lupus Erythematosus Disease Activity Index (2K), (SLEDAI 2K) score of ≥ 4 points. The “clinical” score is the SLEDAI 2K assessment score without the inclusion of points attributable to any blood laboratory results including immunologic measures. Neurologic descriptors of the SLEDAI 2K are not counted towards the SLEDAI 2K study entry criteria. Has received all scheduled vaccines according to local guidelines and Investigator judgement. Live or live-attenuated virus vaccines are not permitted within 1 month prior to screening or during screening. For all other vaccines there must be at least 2 weeks between the vaccination(s) and the date of randomization at Day 1. For male patients: Men who are permanently sterile by bilateral orchidectomy are not required to use contraception. Men whose partner (or potential partner) is a women of childbearing potential*, for the duration of the study (including 30 days after the last dose of study drug) must use a condom. For female patients: Women of childbearing potential* must be willing and able to use a double-barrier contraception (barrier in the meaning of method) with at least one highly effective method of birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when used consistently and correctly for the duration of the study including 4 weeks after the last dose of study drug. Medically accepted methods of contraception in this study are: Combined (oestrogen and progestogen containing) hormonal birth control associated with inhibition of ovulation in combination with male condom. Progestogen-only hormonal birth control associated with inhibition of ovulation in combination with male condom. Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) in combination with male condom Or The patient must have only vasectomized sexual partner(s) (vasectomy at least 1 year prior to enrolment), Or The patient must follow true abstinence from male-female sex. This is defined as being in line with the preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the duration of exposure to IMP; and withdrawal are not acceptable. A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial Exclusion Criteria: Active clinically significant neuropsychiatric SLE or any BILAG A score for a neuropsychiatric manifestation or in the ophthalmic domain within the past 12 months. Drug-induced Lupus. Other autoimmune diseases such as Rheumatoid Arthritis, Crohn’s, scleroderma, psoriasis, Celiac disease, Graves’disease, thyroid disease, with the following exceptions: Sjögren syndrome if this is secondary to their SLE is permissible. Patients with features of mixed connective tissue disease may be included if this is secondary to their SLE and is, in the Investigator’s opinion not considered to be significant. Patients with APS antibodies may be included unless they are excluded due to exclusion anti-coagulation medication (see exclusion criteria below for details) or if they have a history of thromboembolic events or miscarriage. Diabetes if this is considered by the Investigator to be well controlled and there is no evidence of retinopathy or nephropathy. Initiation or change in dose of anti-malarial treatment after the screening visit. Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, dabigatran, heparin, hirudin, etc.) or high dose antiplatelet therapy. Within 2 weeks prior to Screening or during Screening: use of oral corticosteroids greater than (>) 15 mg daily prednisone or an equivalent dose, use of any injectable corticosteroids, or change in dose of corticosteroids. For patients continuing on oral corticosteroids the dose must be stable for 4 weeks prior to randomisation. After consent, initiation or change in dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Initiation of regular nonsteroidal anti-inflammatory drugs (NSAIDs) use within 2 weeks prior to Screening. Regular use defined as 3 consecutive days. Within 2 months prior to Screening or during Screening: initiation of or change in dose of methotrexate, mycophenolate (mofetil or sodium), or azathioprine. Within 4 weeks prior to Screening or during Screening, use of cyclosporine or tacrolimus. Within 3 months prior to Screening or during Screening: use of cyclophosphamide or chlorambucil. Within 3 months prior to Screening or during Screening, use of leflunomide, abatacept, anti-tumor necrosis factor alpha agents, intravenous immunoglobulin, plasmapheresis, or other disease modifying, immunosuppressive, or immunomodulatory therapies not otherwise specified in protocol. Within 12 months prior to screening or during screening: use of anti-CD20 or anti-CD22 biological medications or any other B cell-depleting medication. If a patient has had rituximab more than 6 months ago and has a normal CD-19 count then they may be included. A historic local lab value may be used to confirm this. For B-cell modulating therapies including atacicept these are excluded within 6 months apart from blisibimod and belimumab which are excluded within 3 months. Type I-IFN interferon antagonists such as anifrolumab are excluded within 6 months. Ustekinumab within 6 months of screening. JAK inhibitors within the last 12 months before screening visit. Active clinically significant viral, bacterial or fungal infection, or any serious episode of infection requiring hospitalization within the last 6 months. If the infection is not active or clinical significant or required hospitalization the patient may be included as long as they have not taken antibiotics more than 4 weeks prior to screening. Chronic Hepatitis B, HIV, history of active TB. A patient with an indeterminate or positive TB test result at screening may be enrolled if a thorough investigation by a qualified physician determines that they do not have active TB or untreated latent TB. In the case of Anti-HBc antibody positive result but HBs antigen negative then Hepatitis B DNA can be measured at a local lab. If Hepatitis B DNA is positive the patient will be excluded, if Hepatitis B DNA is negative then the patient can be included. Immunoglobulin G (IgG) less than the lower limit of normal at screening. Estimated glomerular filtration rate of less than (=20% and below lower limit of normal (90 mL/ min/ 1.73m2). Proteinuria > 2 g/d or urine protein/urine creatinine ratio >2 mg/mg at screening. Clinically significant other renal disease based on investigator judgement (e.g. postinfectious GN, pyelonephritis) Major surgery (major according to the investigator’s assessment) performed within 12 weeks prior to randomization or planned during the trial. Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of uterine cervix. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial. Previous randomisation into this trial. Currently enrolled in another investigational device or drug trial, or less than 30 days or 5 half-lives (whichever is longer),since ending another investigational device or drug trial(s) for an oral agent which is not specified in any other exclusion criteria, or less than 12 months since ending another investigational device or drug trial(s) for a biological agent which is not specified in exclusion criteria or receiving other investigational treatment(s). Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes them an unreliable trial patient or unlikely to complete the trial. Women who are pregnant, nursing, or who plan to become pregnant in the timeline of the trial. Uncontrolled hypertension or other haematologic conditions (except SLE). Diabetes mellitus if poorly controlled according to investigator or known diabetic nephropathy or retinopathy. Thrombocyte count at screening 70,000/μl or less. Known hypersensitivity to the study drug or their excipients. Patients with known ocular complications apart from dry eyes and mild cataracts in the opinion of an ophthalmologist. A disease or condition which in the opinion of the investigator may interfere with testing procedures or put the patient at risk when participating in this trial. History of pancreatitis of any aetiology Contacts and Locations Go to Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03771885 Contacts

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(‘childhood’, 11),
(‘tmj’, 11),
(‘anal’, 11),
(‘hospice’, 11),
(‘sufficient’, 11),
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(‘unrelated’, 11),
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(‘insinuate’, 11),
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(‘trade’, 11),
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(‘andy’, 11),
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(‘omaha’, 11),
(‘nebraska’, 11),
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(‘madoff’, 11),
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(‘dillinger’, 11),
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(‘mission’, 12),
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Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

Abstract With the decrease in PSA screening based on the 2011 United States Preventive Services Task Force guidelines and the potential approval of highly sensitive imaging techniques over the next few years, we are likely to see an increasing trend of metastatic prostate cancer diagnosis. Traditional therapy for nonmetastatic prostate cancer (nmPC) has consisted of androgen deprivation therapy (ADT) followed by other hormonal therapy maneuvers, such as anti-androgen withdrawal, herbal preparations, low dose steroids, or ketoconazole. Androgen receptor-axis-targeted therapies (ARAT) were previously only approved for patients with metastatic castration resistant prostate cancer (mCRPC). This has recently changed after reporting of results from the SPARTAN and PROSPER trials, which were conducted in nonmetastatic CRPC (nmCRPC) patients. These studies demonstrated improved metastasis-free survival with apalutamide and enzalutamide, each compared to placebo in a double blind randomized setting. In 2017, the LATITUDE and STAMPEDE studies demonstrated marked survival benefit with early abiraterone and prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) in addition to ADT. Other second-generation AR antagonists are currently in phase 3 trials in mHSPC and nmCRPC. This article summarizes the key clinical trials that led to FDA approval of ARAT in the mHSPC and nmCRPC settings and highlights potential limitations, future directions, and treatment-algorithms when selecting patients for early therapy in mHSPC and NMPC.
https://ift.tt/2SDUuD9

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Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

Therapy of Advanced Prostate Cancer: Targeting the Androgen Receptor Axis in Earlier Lines of Treatment

Abstract With the decrease in PSA screening based on the 2011 United States Preventive Services Task Force guidelines and the potential approval of highly sensitive imaging techniques over the next few years, we are likely to see an increasing trend of metastatic prostate cancer diagnosis. Traditional therapy for nonmetastatic prostate cancer (nmPC) has consisted of androgen deprivation therapy (ADT) followed by other hormonal therapy maneuvers, such as anti-androgen withdrawal, herbal preparations, low dose steroids, or ketoconazole. Androgen receptor-axis-targeted therapies (ARAT) were previously only approved for patients with metastatic castration resistant prostate cancer (mCRPC). This has recently changed after reporting of results from the SPARTAN and PROSPER trials, which were conducted in nonmetastatic CRPC (nmCRPC) patients. These studies demonstrated improved metastasis-free survival with apalutamide and enzalutamide, each compared to placebo in a double blind randomized setting. In 2017, the LATITUDE and STAMPEDE studies demonstrated marked survival benefit with early abiraterone and prednisone in patients with metastatic hormone sensitive prostate cancer (mHSPC) in addition to ADT. Other second-generation AR antagonists are currently in phase 3 trials in mHSPC and nmCRPC. This article summarizes the key clinical trials that led to FDA approval of ARAT in the mHSPC and nmCRPC settings and highlights potential limitations, future directions, and treatment-algorithms when selecting patients for early therapy in mHSPC and NMPC.
https://ift.tt/2SDUuD9

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Lipitor Vs. Crestor: Cholesterol Medication On A Par

Lipitor Vs. Crestor: Cholesterol Medication On A Par

by Mariana Elyard on 25 minutes ago 2 views Some folks have unanswered questions in regards screening procedure and under you will see essentially probably the most frequently requested questions concerning dwelling drug tests. If you take it you is not going to instantly see an finish to your symptoms and drop all the weight you’ve got gained. Writer: Jessica Thomson Prescription glasses are all the time in use prior to now in addition to in the present. Background: [empty] The perfect dosing of albuterol by way of metered-dose inhalers for acute childhood asthma is not effectively established. Moreover, it decreases the levels of triglyceride as well as LDL cholesterol assortments. You might be asked to are available for ( Leo-translate.com.ua ) blood checks and you must meet these obligations. Capsules needs to be stored at or under room temperature between 59-77 degrees F (15-25 levels C). Essential word for site admins: If you’re the administrator of this website note that your entry has been limited since you broke one of many Wordfence advanced blocking rules. However, if you find yourself utilizing the inhaler extra regularly than advised, this may be an indication that the remedy isn’t working successfully. Some negative effects of Nexium might be more serious. Follow the directions for take a look at sprays in the air in case you are utilizing a canister for the primary time or if you haven’t used it for two weeks or more, or if the inhaler has been dropped. Writer: Randy Mark It’s essential to remember of the immense advantages of the CoQ10 nutrient in our physique. I was misdiagnosed with major depression, and prescribed Prozac 20mg. As an outcome of this these receptors won’t see the annihilation indicators beginning from completely different parts of the physique. A diabetes expert who was in town just lately affirmed throughout the dialogue that reasonable indulgence in chocolates may even prevent diabetes and heart disease. I actually have Bipolar 1 disorder. In a Canadian Prozac lawsuit case, it was disclosed that Eli Lilly failed to report to the FDA concerning the findings of two research about psychological instability resulting from Prozac. It’s essential to realise that cheap inns are great for people who’ve a finite funds relating to getaways and trips. Properly, Albuterol is probably the most used bronchodilators nowadays. These high insulin levels cause an increased manufacturing of androgens (male-kind hormones that may cause acne and undesirable hair development) within the ovaries and adrenal glands. Albuterol is ceaselessly administered to babies within the form of a nebulizer. Generic fluoxetine is available in capsule, tablet, and liquid type. I believe Metformin has a profound and really “rejuvenating impact” on glucose and insulin metabolism. Patients with diabetes should also be aware that a wholesome weight improves cholesterol ranges and general well being. These uncomfortable side effects may be severe sufficient to cause therapy to be discontinued in a single out of every 20 patients. They’re going to offer you the very best dosage to make use of, round right here. This treatment may also be supplied in liquid suspension type. Taking a lot lobelia at once can set off vomiting. Don’t adjust your dosage with out the approval of your health care supplier. I like to recommend Metformin to all of my life extension patients who are over 40. Your blood sugar levels might rise while you are on prednisone, possibly causing the body to store more fat. It is the most popular and the most effective prescription used for this purpose as it offers unsurpassed slowing down and stopping associated with hair loss, as well as new growth associated with hair. Consuming sweet alcoholic drinks only raises these levels, which is contrary to the particular intended benefits of this prescription medication. Combined with Groove Agent is a brand new rhythm programming MIDI plug-in, which usually must be one of the most intuitive and music grid editors we’ve seen. Mixed therapy leads to a greater reduction in blood sugar levels than can be attained by possibly class alone. Ventolin HFA is really a medicinal drug that belongs to some class of drugs called bronchodilators. The retailer claims the particular all-natural capsules are capable of increasing sex drive, while prescription drug Viagra is really a medicine used to treat erectile dysfunction. You need to take these antibiotics for among 10 days to two or three weeks to completely treat the infection and prevent complications. Select one that best suits your lifestyle, also keep in mind to add some funky shower drape holders I’m conscious that evaluating the e-book utilizing a film is unfair, so, only one side: Cossette is at effectiveness of valtrex nighttime hauling a pail weighty as herself and the duty immediately turns into lighting. They work to decrease cholesterol ranges by reducing the absorption and manufacturing of cholesterol. Metformin can be used to deal with (PCOS) or Polycystic ovary syndrome. What are these symptoms and why do they happen? Researchers have proven the sort 2 diabetes drug metformin helps boost good intestine micro organism, in line with a brand new examine. Metformin was related to a reduction of most cancers, cardiovascular disease, frailty-associated illness and depression in all groups. The mortality charges have been also lower in all courses amongst metformin users. 7% in a management group. This was in comparison to the 3. This web site is for information purposes solely. Withdrawal Symptoms after Selective Serotonin Reuptake Inhibitor Discontinuation: A systematic Review. Normally mild renal, hepatic, coeliac, and chemokine launch of difficulty in each for physiotherapy, group exercise tolerance, existing disease? If you have any concerns pertaining to where and ways to make use of www.lmfafootball.ca ( www.lmfafootball.ca ), you can call us at our internet site.

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