Budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age.

Limitations of Use:

Dosing recommendations based on previous therapy are as follows:

In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.

Budesonide inhalation suspension should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are NOT recommended.

The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Patient Counseling Information (17.1)].

A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U.S. controlled clinical studies. The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.

Budesonide inhalation suspension is available in two strengths, each containing 2 mL: 0.25 mg/2 mL and 0.5 mg/2 mL. Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose ampules, together with patient instructions for use. There are 30 budesonide inhalation suspension ampules in a carton. Each single-dose budesonide inhalation suspension ampule contains 2 mL of sterile liquid suspension.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is available in two strengths, each containing 2 mL: 0.25 mg/2 mL and 0.5 mg/2 mL. Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of five single-dose ampules, together with patient instructions for use. There are 30 budesonide inhalation suspension ampules in a carton. Each single-dose budesonide inhalation suspension ampule contains 2 mL of sterile liquid suspension." }

The use of budesonide inhalation suspension is contraindicated in the following conditions:

{ "type": "p", "children": [], "text": "The use of budesonide inhalation suspension is contraindicated in the following conditions:" }

{ "type": "ul", "children": [ "Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.", "Hypersensitivity to budesonide or any of the ingredients of budesonide inhalation suspension\n \n [see\n \n Warnings and Precautions (5.3),\n \n Description (11)and\n \n Adverse Reactions (6.2)].\n \n \n" ], "text": "" }

In clinical trials with budesonide inhalation suspension localized infections with Candida albicansoccurred in the mouth and pharynx in some patients. The incidences of localized infections of Candida albicanswere similar between the placebo and budesonide inhalation suspension treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with budesonide inhalation suspension. Patients should rinse the mouth after inhalation of budesonide inhalation suspension.

Budesonide inhalation suspension is not a bronchodilator and is not indicated for the rapid relief of acute bronchospasm or other acute episodes of asthma.

Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with budesonide inhalation suspension. During such episodes, patients may require therapy with oral corticosteroids.

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension. Discontinue budesonide inhalation suspension if such reactions occur [see Contraindications (4)].

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered.

The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied. However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with 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 budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (ie, beta 2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥5.0 (gpELISA value) in response to the vaccination was similar in patients treated with 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.

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.

Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA)-axis function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although budesonide inhalation suspension may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instructions. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to budesonide inhalation suspension. Initially, budesonide inhalation suspension should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid may be initiated by reducing the daily or alternate daily dose. Further incremental reductions may be made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 25% of the prednisone dose or its equivalent. A slow rate of withdrawal is strongly recommended.

Lung function (FEV 1or 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 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 (2) ].

During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

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 budesonide inhalation suspension. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with budesonide inhalation suspension should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism, and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of budesonide inhalation suspension should be reduced slowly, consistent with accepted procedures for tapering of systemic corticosteroids and for management of asthma.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), should be monitored and treated with established standards of care.

Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving budesonide inhalation suspension routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including budesonide, each patient should be titrated to his/her lowest effective dose [see Use In Specific Populations (8.4)].

Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If acute bronchospasm occurs following dosing with budesonide inhalation suspension, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with budesonide inhalation suspension should be discontinued and alternate therapy instituted.

In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.

Caution should be exercised when considering the coadministration of budesonide suspension inhalation with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The incidence of common adverse reactions is based on three double-blind, placebo-controlled, randomized U.S. clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients ≥12 months and <2 years of age; 225 patients ≥2 and <4 years of age; and 622 patients ≥4 and ≤8 years of age) were treated with budesonide inhalation suspension (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for budesonide inhalation suspension was comparable to that reported for placebo. The following table shows the incidence of adverse events in U.S. controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators and/or inhaled corticosteroids. This population included a total of 605 male and 340 female patients and 78.4% were Caucasian, 13.8% African American, 5.5% Hispanic and 2.3% Other.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 1 – Adverse Reactions occurring at an incidence of ≥3% in at least one active treatment group where the incidence was higher with budesonide inhalation suspension than placebo</span> </caption> <colgroup> <col align="left" valign="middle" width="40%"/> <col align="center" valign="middle" width="20%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="20%"/> </colgroup> <thead> <tr class="Botrule First First"> <th align="center" class="Lrule Rrule" rowspan="2">Adverse Events</th><th align="center" class="Rrule" rowspan="2">Vehicle Placebo (n=227) %</th><th align="center" class="Rrule" colspan="3"> <br/> Budesonide Inhalation Suspension Total Daily Dose </th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">0.25 mg (n=178) %</th><th align="center" class="Lrule Rrule">0.5 mg (n=223) %</th><th align="center" class="Rrule">1 mg (n=317) %</th> </tr> </thead> <tbody> <tr class="Botrule First First"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Respiratory System Disorder</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Respiratory Infection</td><td align="center" class="Rrule">36</td><td align="center" class="Rrule">34</td><td align="center" class="Rrule">35</td><td class="Rrule">38</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Rhinitis</td><td align="center" class="Rrule">9</td><td align="center" class="Rrule">7</td><td align="center" class="Rrule">11</td><td class="Rrule">12</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Coughing</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">9</td><td class="Rrule">8</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Resistance Mechanism Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Otitis Media</td><td align="center" class="Rrule">11</td><td align="center" class="Rrule">12</td><td align="center" class="Rrule">11</td><td class="Rrule">9</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Viral Infection</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">5</td><td class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Moniliasis</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">3</td><td class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Gastrointestinal System Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Gastroenteritis</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">5</td><td align="center" class="Rrule">5</td><td class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td><td class="Rrule">4</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Diarrhea</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">4</td><td class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Abdominal Pain</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">2</td><td class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Hearing and Vestibular Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Ear Infection</td><td align="center" class="Rrule">4</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td><td class="Rrule">5</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Platelet, Bleeding and Clotting Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Epistaxis</td><td align="center" class="Rrule">1</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">4</td><td class="Rrule">3</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Vision Disorders</span></td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Conjunctivitis</td><td align="center" class="Rrule">2</td><td align="center" class="Rrule">&lt; 1</td><td align="center" class="Rrule">4</td><td class="Rrule">2</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule" colspan="5"><span class="Bold">Skin and Appendages Disorders</span></td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Rash</td><td align="center" class="Rrule">3</td><td align="center" class="Rrule">&lt; 1</td><td align="center" class="Rrule">4</td><td class="Rrule">2</td> </tr> </tbody> </table></div>

The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one budesonide inhalation suspension treatment group where the incidence was higher with budesonide inhalation suspension than with placebo, regardless of relationship to treatment.

Blood and lymphatic system disorders:cervical lymphadenopathy

Ear and labyrinth disorders:earache

General disorders and administration site conditions:fatigue, flu-like disorder

Immune system disorders:allergic reaction

Infections and infestations:eye infection, herpes simplex, external ear infection, infection

Injury, poisoning and procedural complication:fracture

Metabolism and nutrition disorders:anorexia

Musculoskeletal and connective tissue disorders:myalgia

Nervous system disorders:hyperkinesia

Psychiatric disorders:emotional lability

Respiratory, thoracic, and mediastinal disorders:chest pain, dysphonia, stridor

Skin and subcutaneous tissue disorders:contact dermatitis, eczema, pustular rash, pruritus, purpura

The incidence of reported adverse events was similar between the 447 budesonide inhalation suspension treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies.

The following adverse reactions have been reported during post-approval use of budesonide inhalation suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with budesonide inhalation suspension.

Endocrine disorders:symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.6)]

Eye disorders:cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)]

General disorders and administration site conditions:fever, pain

Immune system disorders:immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria [see Contraindications (4)and Warnings and Precautions (5.10)]

Infection and Infestation:sinusitis, pharyngitis, bronchitis

Musculoskeletal and connective tissue disorders:avascular necrosis of the femoral head, osteoporosis, growth suppression

Nervous system disorders:headache

Psychiatric disorders:psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety

Respiratory, thoracic, and mediastinal disorders:cough, dysphonia and throat irritation

Skin and subcutaneous tissue disorders:skin bruising, facial skin irritation

Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for budesonide inhalation suspension [see Warnings and Precautions (5.8)and Use In Specific Populations (8.4)].

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 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 (5.12)and Clinical Pharmacology(12.3)].

Risk Summary

There are no adequate well-controlled studies of budesonide inhalation suspension in pregnant women. However, there are published studies on the use of budesonide, the active ingredient in budesonide inhalation suspension, in pregnant women. In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the maximum recommended human daily inhalation dose (MRHDID), but these effects were not seen in rats that received inhaled doses approximately 2 times the MRHDID (see Data). Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans. The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery There are no well-controlled human studies that have investigated the effects of budesonide inhalation suspension during labor and delivery.

Data

Human Data 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 (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). These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Animal Data

In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide 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 doses 0.2 times the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.05 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 5 mcg/kg/day).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 5 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 250 mcg/kg/day).

In a peri- and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses less than 0.2 times the MRHDID and higher (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Risk Summary

There are no available data on the effects of budesonide inhalation suspension on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide inhalation suspension and any potential adverse effects on the breastfed infant from budesonide inhalation suspension or from the underlying maternal condition.

Data

Human data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology(12.3)].

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 (12.2),  Adverse Reactions (6.1)].

A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg 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 budesonide inhalation suspension versus placebo. However, on an individual basis, 7 patients in this study (6 in the 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 (12.2)]. Pneumonia was observed more frequently in patients treated with budesonide inhalation suspension than in patients treated with placebo, (N = 2, 1, and 0) in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo groups, respectively.

A dose dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the budesonide inhalation suspension 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and budesonide inhalation suspension 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and budesonide inhalation suspension 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of budesonide inhalation suspension in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

In a study of asthmatic children 5 to 12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with the budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.

The growth of pediatric patients receiving inhaled corticosteroids, including 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 budesonide inhalation suspension each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2)and Warnings and Precautions (5.8)].

Of the 215 patients in 3 clinical trials of budesonide inhalation suspension in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.

Formal pharmacokinetic studies using budesonide inhalation suspension have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.

The potential for acute toxic effects following overdose of 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 (5.6)].

{ "type": "p", "children": [], "text": "The potential for acute toxic effects following overdose of 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 [\n \n see\n \n Warnings and Precautions (5.6)].\n \n \n" }

Budesonide, the active component of budesonide inhalation suspension, 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).

{ "type": "p", "children": [], "text": "Budesonide, the active component of budesonide inhalation suspension, 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 25H 34O 6and its molecular weight is 430.5. Its structural formula is:

{ "type": "p", "children": [], "text": "The empirical formula of budesonide is C\n \n 25H\n \n 34O\n \n 6and its molecular weight is 430.5. Its structural formula is: \n \n\n" }

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 coeffecient between octanol and water at pH 7.4 is 1.6 x 10 3.

{ "type": "p", "children": [], "text": "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 coeffecient between octanol and water at pH 7.4 is 1.6 x 10\n \n 3.\n\n " }

Budesonide inhalation suspension is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection. Two dose strengths are available in single-dose ampules: 0.25 mg and 0.5 mg per 2 mL ampule. For budesonide inhalation suspension, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, under in vitroconditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. Budesonide inhalation suspension should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces [see Dosage and Administration (2)].

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection. Two dose strengths are available in single-dose ampules: 0.25 mg and 0.5 mg per 2 mL ampule. For budesonide inhalation suspension, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, under\n \n in vitroconditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. Budesonide inhalation suspension should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces\n \n [see\n \n Dosage and Administration (2)].\n \n \n" }

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitroand 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 clinical significance of these findings is unknown.

The activity of budesonide inhalation suspension 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 vitrostudies 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., histamine, 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 anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85 to 95%) and the low potency of metabolites (see below).

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.

Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks.

Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine 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 1following inhaled allergen challenge.

HPA Axis Effects

The effects of 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 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 budesonide inhalation suspension 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 budesonide inhalation suspension or placebo. A total of 28, 17, and 31 patients in the 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 budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0.5 mg, 2 of whom received 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 budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L.

The effects of budesonide inhalation suspension at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43 to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.

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 Precautions (5.5)].

Absorption:

In asthmatic children 4 to 6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of 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 C max, is similar for young children and adults after inhalation of the same dose of budesonide inhalation suspension.

Distribution:

In asthmatic children 4 to 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 to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. 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 vitrostudies 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 in vitroand in vivometabolic 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 to 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 (8.2)].

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 (5.12),  Drug Interactions (7.1)].

Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.04 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis). 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis). 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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2basis).

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.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m 2basis. 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 MRHDID in adults on a mcg/m 2basis. No such effects were noted at 5 mcg/kg (approximately 0.04 times the MRHDID in adults on a mcg/m 2basis).

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy of 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 179.5% 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 to 12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with budesonide inhalation suspension compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

Statistically significant increases in FEV 1compared to placebo were observed with 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).

Patients Receiving Once-Daily or Twice-Daily Dosing

The efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 3. Budesonide inhalation suspension 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.

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 budesonide inhalation suspension administered on either a once daily or twice-daily schedule. When all measures are considered together, the evidence is stronger for twice-daily dosing [see Dosage and Administration (2)].

Budesonide inhalation suspension should be stored upright at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP], and protected from light. When an envelope has been opened, the shelf life of the unused ampules is 2 weeks when protected. After opening the aluminum foil envelope, the unused ampules should be returned to the aluminum foil envelope to protect them from light. Any opened ampule must be used promptly. Gently shake the ampule using a circular motion before use. Keep out of reach of children. Do not freeze.

Patients should be advised that 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 budesonide inhalation suspension and, therefore, are not recommended. The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Dosage and Administration (2)].

Patients should be advised that localized infections with Candida albicansoccurred 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 budesonide inhalation suspension, but at times therapy with budesonide inhalation suspension may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)].

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 beta 2-agonist such as albuterol.

(The healthcare professional should provide that patient with such medication and instruct the patient in how it should be used) Patients should be clearly instructed to notify their healthcare professional immediately if they experience any of the following:

Patients should not stop therapy with budesonide inhalation suspension without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2)].

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension. Discontinue budesonide inhalation suspension if such reactions occur [see Contraindications (4); Warning and Precautions (5.3)].

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 (5.4)].

Patients should be advised that 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 budesonide inhalation suspension [see Warnings and Precautions (5.6)].

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 (5.7)].

Patients should be informed that orally inhaled corticosteroids, including budesonide, 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 (5.8)].

Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts and glaucoma); regular eye examinations should be considered [see Warnings and Precautions (5.9)].

Patients should be advised to use budesonide inhalation suspension at regular intervals once or twice a day, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 4 to 6 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the conditions worsens, patients should be instructed to contact their healthcare professional.

See accompanying Patient Information and Instructions for Use.

Issued: 02/2025

Distributed by: Rising Pharma Holdings, Inc. East Brunswick, NJ 08816

{ "type": "p", "children": [], "text": "\nDistributed by:\n Rising Pharma Holdings, Inc. \n East Brunswick, NJ 08816\n\n " }

Manufactured by: Nephron Pharmaceutical Corporation West Columbia, SC 29172 Call 1-800-443-4313

{ "type": "p", "children": [], "text": "Manufactured by: \n Nephron Pharmaceutical Corporation \n West Columbia, SC 29172 \n Call 1-800-443-4313\n " }

Budesonide (bew DEH so nide)

{ "type": "p", "children": [], "text": "Budesonide (bew DEH so nide)" }

(budesonide) inhalation suspension

{ "type": "p", "children": [], "text": "(budesonide) inhalation suspension" }

2 mL ampules containing 0.25 mg or 0.5 mg

{ "type": "p", "children": [], "text": "2 mL ampules containing 0.25 mg or 0.5 mg" }

For inhalation only.

{ "type": "p", "children": [], "text": "\nFor inhalation only.\n" }

Do not swallow.

{ "type": "p", "children": [], "text": "\nDo not swallow.\n" }

Only use budesonide inhalation suspension with a jet nebulizer machine that is connected to an air compressor. Do not use with an ultrasonic nebulizer.

{ "type": "p", "children": [], "text": "\nOnly use budesonide inhalation suspension with a jet nebulizer machine that is connected to an air compressor. Do not use with an ultrasonic nebulizer.\n" }

Read the Patient Information that comes with budesonide inhalation suspension before your child starts using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your child's medical condition or treatment. If you have any questions about budesonide inhalation suspension, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Read the Patient Information that comes with budesonide inhalation suspension before your child starts using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your child's medical condition or treatment. If you have any questions about budesonide inhalation suspension, ask your healthcare provider or pharmacist." }

What is budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nWhat is budesonide inhalation suspension?\n" }

Budesonide inhalation suspension is an inhaled corticosteroid medicine. Budesonide inhalation suspension is a long-term maintenance medicine used to control and prevent asthma symptoms in children ages 12 months to 8 years.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is an inhaled corticosteroid medicine. Budesonide inhalation suspension is a long-term maintenance medicine used to control and prevent asthma symptoms in children ages 12 months to 8 years." }

Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms. Budesonide inhalation suspension helps reduce swelling and inflammation in the lungs, and helps keep the airways open to reduce asthma symptoms.

{ "type": "p", "children": [], "text": "Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms. Budesonide inhalation suspension helps reduce swelling and inflammation in the lungs, and helps keep the airways open to reduce asthma symptoms." }

Budesonide inhalation suspension does not treat the sudden symptoms (wheezing, cough, shortness of breath, and chest pain or tightness) of an asthma attack. Always have a short-acting beta 2-agonist medicine (rescue inhaler) with you to treat sudden symptoms. If your child does not have an inhaled, short-acting bronchodilator, ask your healthcare provider to have one prescribed for your child.

{ "type": "p", "children": [], "text": "\nBudesonide inhalation suspension does not treat the sudden symptoms (wheezing, cough, shortness of breath, and chest pain or tightness) of an asthma attack. Always have a short-acting beta\n \n 2-agonist medicine (rescue inhaler) with you to treat sudden symptoms. If your child does not have an inhaled, short-acting bronchodilator, ask your healthcare provider to have one prescribed for your child.\n \n \n" }

It is not known if budesonide inhalation suspension is safe or effective in children younger than 12 months or older than 8 years.

{ "type": "p", "children": [], "text": "It is not known if budesonide inhalation suspension is safe or effective in children younger than 12 months or older than 8 years." }

Who should not use budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nWho should not use budesonide inhalation suspension?\n" }

Do not use budesonide inhalation suspension:

{ "type": "p", "children": [], "text": "\nDo not use budesonide inhalation suspension:\n" }

{ "type": "ul", "children": [ "\nto treat sudden symptoms of asthma\n", "\nif your child is allergic to budesonide or any of the ingredients in budesonide inhalation suspension. \n \n See the end of this leaflet for a complete list of ingredients in budesonide inhalation suspension.\n \n" ], "text": "" }

What should I tell my healthcare provider before using budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before using budesonide inhalation suspension?\n" }

Before your child uses budesonide inhalation suspension, tell your healthcare provider if your child:

{ "type": "p", "children": [], "text": "Before your child uses budesonide inhalation suspension, tell your healthcare provider if your child:" }

{ "type": "ul", "children": [ "has an allergy. See the section \"Who should not use budesonide inhalation suspension?\" There is a complete list of ingredients in budesonide inhalation suspension at the end of this leaflet.", "has or recently had chicken pox or measles, or has recently been near anyone with chicken pox or measles.", "has or had tuberculosis of the respiratory tract.", "has certain kinds of infections that have not been treated, including:\n \n \nfungal infections\nbacterial infections\nviral infections\nparasitic infections\nherpes simplex infection of the eye (ocular herpes simplex)\n\n" ], "text": "" }

Budesonide inhalation suspension may not be right for children who have had any of these types of infections.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension may not be right for children who have had any of these types of infections." }

{ "type": "ul", "children": [ "has decreased bone mineral density (bone strength). Your child is at risk for decreased bone mineral density if he or she:\n \n \nis inactive for a long period of time\nhas a family history of osteoporosis\ndoes not eat well (poor nutrition)\ntakes bone thinning medicines (such as anticonvulsant medicines or corticosteroids) for a long time.\n\n", "has an eye problem such as increased pressure in the eye, glaucoma or cataracts.", "has liver problems.", "is planning to have surgery.", "has any other medical conditions.", "is pregnant or plans to become pregnant. It is not known if budesonide inhalation suspension will harm your unborn baby.", "is breast-feeding or plans to breast-feed. Budesonide inhalation suspension can pass into breast milk. You and your healthcare provider should decide if you will use budesonide inhalation suspension or breast-feed." ], "text": "" }

Tell your healthcare provider about all the medicine your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about all the medicine your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements." }

Using budesonide inhalation suspension with certain other medicines may affect each other causing side effects. Especially tell your healthcare provider if your child takes:

{ "type": "p", "children": [], "text": "Using budesonide inhalation suspension with certain other medicines may affect each other causing side effects. Especially tell your healthcare provider if your child takes:" }

{ "type": "ul", "children": [ "corticosteroids", "anti-seizure medicine (anticonvulsants)", "medicines that suppress the immune system (immunosuppressant)", "ketoconazale (Nizoral)", "certain medicines that can affect how your liver breaks down medicine" ], "text": "" }

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

{ "type": "p", "children": [], "text": "Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure." }

Know the medicines your child takes. Keep a list of them and show it to your healthcare provider and pharmacist when your child gets a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines your child takes. Keep a list of them and show it to your healthcare provider and pharmacist when your child gets a new medicine." }

How should I use budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nHow should I use budesonide inhalation suspension?\n" }

{ "type": "ul", "children": [ "Use budesonide inhalation suspension exactly as prescribed by your healthcare provider. Your child must use budesonide inhalation suspension regularly for it to work.", "Budesonide inhalation suspension comes in two strengths. Your healthcare provider has prescribed the strength that is best for your child.", "Do not stop using budesonide inhalation suspension and do not change your child's dose of budesonide inhalation suspension without talking to your healthcare provider.", "Budesonide inhalation suspension is for inhaled use only. Use budesonide inhalation suspension with a jet nebulizer connected to an air compressor set up with a mouthpiece or face mask. Do not use an ultrasonic nebulizer to give budesonide inhalation suspension.", "Do not mix budesonide inhalation suspension with other nebulizer medicines. If your child uses another medicine by inhalation to treat asthma, talk with your healthcare provider for instructions on when to use the other medicine.", "If your child misses a dose, just give the next regularly scheduled dose when it is due. Do not use budesonide inhalation suspension more often than has been prescribed.", "Improvement in the control of asthma symptoms with budesonide inhalation suspension can occur within 2 to 8 days. It may take up to 4 to 6 weeks before maximum improvement is seen.", "Make sure your child always has a short-acting beta\n \n 2-agonist medicine with him or her. Your child should use the short-acting beta\n \n 2-agonist medicine for breathing problems between doses of budesonide inhalation suspension or if a sudden asthma attack happens.\n \n " ], "text": "" }

Call your healthcare provider right away if:

{ "type": "p", "children": [], "text": "Call your healthcare provider right away if:" }

{ "type": "ul", "children": [ "\n\nthe short-acting rescue medicine does not work as well for relieving asthma symptoms.\nyour child needs to use the short-acting rescue medicines more often than usual.\nyour child's breathing problems worsen with budesonide inhalation suspension.\n\n" ], "text": "" }

{ "type": "ul", "children": [ "Rinse your child's mouth with water and have him or her spit the water out after each budesonide inhalation suspension treatment. Do not swallow the water. This will lessen the chance of getting a fungal infection (thrush) in the mouth.", "If your child has used long-term corticosteroids and the dose is now being lowered or stopped, a warning card should be carried stating that your child may need corticosteroids during times of stress or during an asthma attack that does not get better with bronchodilator medicines.", "Your healthcare provider may check your child's blood, breathing and do eye exams while using budesonide inhalation suspension", "Read the Patient Information and Instructions for Use at the end of this leaflet for detailed instructions about how to use budesonide inhalation suspension." ], "text": "" }

What are the possible side effects of budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of budesonide inhalation suspension?\n" }

Budesonide inhalation suspension may cause serious side effects including:

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension may cause serious side effects including:" }

{ "type": "ul", "children": [ "Thrush (candida), a fungal infection in your mouth and throat. Tell your healthcare provider if your child has any redness or white colored patches in the mouth or throat.", "Worsening of asthma or sudden asthma attacks.", "Allergic reactions. Tell your healthcare provider or get medical help right away if your child has:\n \n \nskin rash, redness or swelling\nsevere itching\nswelling of the face, mouth and tongue\ntrouble breathing or swallowing\nchest pain\nanxiety (feeling of doom)\n\n", "Immune system effects and a higher chance of infections. Your child is more likely to get infections when taking medicines that weaken the immune system. Symptoms of infection may include: fever, pain, aches, chills, feeling tired, nausea and vomiting.Tell your healthcare provider about any signs of infection while your child uses budesonide inhalation suspension.", "Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency include tiredness, weakness, nausea and vomiting, and low blood pressure.", "Decrease in bone mineral density (bone strength). Your healthcare provider may want to check your child for this during treatment with budesonide inhalation suspension.", "Slowed or delayed growth problems. Your child's healthcare provider may want to monitor your child's growth while using budesonide inhalation suspension.", "Eye problems, including glaucoma and cataracts. Your child's healthcare provider may suggest eye exams while using budesonide inhalation suspension.", "\nIncreased wheezing right after taking budesonide inhalation suspension. Always have a fast-acting inhaled bronchodilator medicine with you to treat sudden wheezing\n" ], "text": "" }

Call your healthcare provider or get medical help right away if your child has any of the serious side effects listed above.

{ "type": "p", "children": [], "text": "Call your healthcare provider or get medical help right away if your child has any of the serious side effects listed above." }

The most common side effects of budesonide inhalation suspension include:

{ "type": "p", "children": [], "text": "The most common side effects of budesonide inhalation suspension include:" }

{ "type": "ul", "children": [ "respiratory infections. Symptoms may include stuffy nose, sore nose and throat.", "runny nose", "cough", "viral infections", "viral irritation and inflammation of the stomach and intestine (gastroenteritis). Gastroenteritis symptoms may include: stomach area pain, diarrhea, nausea and vomiting, and loss of appetite.", "ear infections", "nosebleed", "pink eye (conjunctivitis)", "rash" ], "text": "" }

Tell your healthcare provider if your child has any side effect that bothers him or her or that does not go away.

{ "type": "p", "children": [], "text": "Tell your healthcare provider if your child has any side effect that bothers him or her or that does not go away." }

For more information, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "For more information, ask your healthcare provider or pharmacist." }

Call your healthcare provider for medical advice about side effects.

{ "type": "p", "children": [], "text": "Call your healthcare provider for medical advice about side effects." }

To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." }

How should I store budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nHow should I store budesonide inhalation suspension?\n" }

{ "type": "ul", "children": [ "Store budesonide inhalation suspension in an upright position between 68°F to 77°F (20°C to 25°C)", "Keep budesonide inhalation suspension in the aluminium foil envelope to protect from light until ready to use.", "After a budesonide inhalation suspension ampule is opened it should be used right away.", "Budesonide inhalation suspension ampules can be stored for 2 weeks after opening the protective aluminum foil envelope.", "Throw away budesonide inhalation ampules if not used within 2 weeks of opening the protective aluminum foil envelope.", "Do not refrigerate or freeze." ], "text": "" }

Keep budesonide inhalation suspension and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep budesonide inhalation suspension and all medicines out of the reach of children.\n\n " }

General Information about budesonide inhalation suspension

{ "type": "p", "children": [], "text": "\nGeneral Information about budesonide inhalation suspension\n" }

Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use budesonide inhalation suspension for a condition for which it was not prescribed. Do not give budesonide inhalation suspension to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use budesonide inhalation suspension for a condition for which it was not prescribed. Do not give budesonide inhalation suspension to other people, even if they have the same symptoms that you have. It may harm them." }

This Patient Information leaflet summarizes the most important information about budesonide inhalation suspension if you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about budesonide inhalation suspension that is written for health professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about budesonide inhalation suspension if you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about budesonide inhalation suspension that is written for health professionals." }

For more information call Rising Pharma Holdings, Inc. at 1-844-874-7464.

{ "type": "p", "children": [], "text": "For more information call Rising Pharma Holdings, Inc. at 1-844-874-7464." }

What are the ingredients in budesonide inhalation suspension?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in budesonide inhalation suspension?\n" }

Active ingredient: budesonide.

{ "type": "p", "children": [], "text": "Active ingredient: budesonide." }

Inactive ingredients: citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection.

{ "type": "p", "children": [], "text": "Inactive ingredients: citric acid, edetate disodium dihydrate, polysorbate 80, sodium chloride, sodium citrate, and water for injection." }

Patient Instructions for Use

{ "type": "p", "children": [], "text": "\nPatient Instructions for Use\n" }

Important:

{ "type": "p", "children": [], "text": "\nImportant:\n" }

Budesonide inhalation suspension is only for use with a jet nebulizer machine. Make sure you know how to use your jet nebulizer machine before your child uses budesonide inhalation suspension.

{ "type": "p", "children": [], "text": "\nBudesonide inhalation suspension is only for use with a jet nebulizer machine. Make sure you know how to use your jet nebulizer machine before your child uses budesonide inhalation suspension.\n" }

Budesonide inhalation suspension is a liquid that is turned into a mist by a nebulizer and inhaled into the lungs.

{ "type": "p", "children": [], "text": "\nBudesonide inhalation suspension is a liquid that is turned into a mist by a nebulizer and inhaled into the lungs.\n" }

The face mask should be properly adjusted to optimize delivery and to avoid exposing the eyes to the nebulized medication. Corticosteroid effects on the skin can be avoided if the face is washed after the use of a mask.

{ "type": "p", "children": [], "text": "\nThe face mask should be properly adjusted to optimize delivery and to avoid exposing the eyes to the nebulized medication. Corticosteroid effects on the skin can be avoided if the face is washed after the use of a mask.\n" }

1. Budesonide inhalation solution comes in a sealed protective aluminium foil envelope.

{ "type": "p", "children": [], "text": "1. Budesonide inhalation solution comes in a sealed protective aluminium foil envelope." }

{ "type": "ul", "children": [ "Do not open the sealed pouch until you are ready to use a dose of budesondie inhalation suspension", "Open the sealed envelope along the dotted line and take out 1 single-dose ampule from the strip. See Figure 1.", "Record the date that you opened the foil on the envelope in the space provided." ], "text": "" }

Return the unopened budesonide inhalation suspension ampules on the strip back into the foil envelope before storing.

{ "type": "p", "children": [], "text": "Return the unopened budesonide inhalation suspension ampules on the strip back into the foil envelope before storing." }

2. Gently shake the budesonide inhalation suspension ampule using a circular motion as shown in Figure 2.

{ "type": "p", "children": [], "text": "2. Gently shake the budesonide inhalation suspension ampule using a circular motion as shown in Figure 2." }

3. Hold the budesonide inhalation suspension ampule upright without squeezing the ampule and open by twisting off the top as shown in Figure 3.

{ "type": "p", "children": [], "text": "3. Hold the budesonide inhalation suspension ampule upright without squeezing the ampule and open by twisting off the top as shown in Figure 3." }

4. Place the open end of the budesonide inhalation suspension ampule into the nebulizer cup (reservoir) and slowly squeeze all of the medicine from the ampule into the nebulizer medicine cup as shownin Figure 4. Throw away the empty ampule.

{ "type": "p", "children": [], "text": "4. Place the open end of the budesonide inhalation suspension ampule into the nebulizer cup (reservoir) and slowly squeeze all of the medicine from the ampule into the nebulizer medicine cup as shownin Figure 4. Throw away the empty ampule." }

5. Use your jet nebulizer as directed.

{ "type": "p", "children": [], "text": "5. Use your jet nebulizer as directed." }

Distributed by:

{ "type": "p", "children": [], "text": "\nDistributed by:\n" }

Rising Pharma Holdings, Inc.

{ "type": "p", "children": [], "text": "Rising Pharma Holdings, Inc." }

East Brunswick, NJ 08816

{ "type": "p", "children": [], "text": "East Brunswick, NJ 08816" }

Manufactured By:

{ "type": "p", "children": [], "text": "Manufactured By:" }

nephron pharmaceuticals corporation

{ "type": "p", "children": [], "text": "nephron pharmaceuticals corporation" }

West Columbia, SC 29172

{ "type": "p", "children": [], "text": "West Columbia, SC 29172" }

For Customer Service, Call 1-844-874-7464

{ "type": "p", "children": [], "text": "\nFor Customer Service, \n Call 1-844-874-7464\n \n" }

IC 3010

{ "type": "p", "children": [], "text": "IC 3010" }

Issued:02/2025

{ "type": "p", "children": [], "text": "\nIssued:02/2025\n\n " }

Principle Display - Pouch Label (5 Ampules Per Foil Pouch)

{ "type": "p", "children": [], "text": "\nPrinciple Display - Pouch Label (5 Ampules Per Foil Pouch)\n" }

NDC 64980-638-03

{ "type": "p", "children": [], "text": "\nNDC 64980-638-03\n" }

Principle Display - Carton Label (30 Ampules, 5 Ampules Per Foil Pouch)

{ "type": "p", "children": [], "text": "\nPrinciple Display - Carton Label (30 Ampules, 5 Ampules Per Foil Pouch)\n" }

NDC 64980-638-03

{ "type": "p", "children": [], "text": "\nNDC 64980-638-03\n" }

Principle Display - Pouch Label (5 Ampules Per Foil Pouch)

{ "type": "p", "children": [], "text": "\nPrinciple Display - Pouch Label (5 Ampules Per Foil Pouch)\n" }

NDC 64980-639-03

{ "type": "p", "children": [], "text": "\nNDC 64980-639-03\n" }

Principle Display - Carton (30 Ampules, 5 Ampules Per Foil Pouch)

{ "type": "p", "children": [], "text": "\nPrinciple Display - Carton (30 Ampules, 5 Ampules Per Foil Pouch)\n" }

NDC 64980-639-03

{ "type": "p", "children": [], "text": "\nNDC 64980-639-03\n" }

Budesonide delayed-release capsules are indicated for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon in patients 8 years of age and older. 

Budesonide delayed-release capsules are indicated for the maintenance of clinical remission of mild to moderate Crohn’s disease involving the ileum and/or the ascending colon for up to 3 months in adults. 

The recommended dosage of budesonide delayed-release capsules are: 

Adults: 9 mg orally once daily for up to 8 weeks. Repeated 8-week courses of budesonide delayed-release capsules can be given for recurring episodes of active disease. 

Pediatric patients 8 to 17 years who weigh more than 25 kg: 9 mg orally once daily for up to 8 weeks, followed by 6 mg once daily for 2 weeks.

The recommended dosage in adults, following an 8-week course(s) of treatment for active disease and once the patient’s symptoms are controlled (CDAI less than 150), is budesonide delayed-release capsules 6 mg orally once daily for maintenance of clinical remission up to 3 months. If symptom control is still maintained at 3 months an attempt to taper to complete cessation is recommended. Continued treatment with budesonide delayed-release capsules 6 mg for more than 3 months has not been shown to provide substantial clinical benefit. 

Patients with mild to moderate active Crohn’s disease involving the ileum and/or ascending colon have been switched from oral prednisolone to budesonide delayed-release capsules with no reported episodes of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should begin concomitantly with initiating budesonide delayed-release capsules treatment. 

Consider reducing the dosage of budesonide delayed-release capsules to 3 mg once daily for adult patients with moderate hepatic impairment (Child-Pugh Class B). Avoid use in patients with severe hepatic impairment (Child-Pugh Class C) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)].

Budesonide delayed-release capsules 3 mg are hard gelatin capsules with an opaque light gray body imprinted “778” and an opaque maroon cap imprinted “AMNEAL” with black ink. 

{ "type": "p", "children": [], "text": "Budesonide delayed-release capsules 3 mg are hard gelatin capsules with an opaque light gray body imprinted “778” and an opaque maroon cap imprinted “AMNEAL” with black ink. " }

Budesonide delayed-release capsules are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide delayed-release capsules. Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions (6.2)]. 

{ "type": "p", "children": [], "text": "Budesonide delayed-release capsules are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide delayed-release capsules. Serious hypersensitivity reactions, including anaphylaxis have occurred [see Adverse Reactions (6.2)]. " }

Systemic effects such as hypercorticism and adrenal axis suppression may occur with use of corticosteroids, including budesonide [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].  

Pediatric patients with Crohn’s disease have a slightly higher systemic exposure of budesonide and increased cortisol suppression than adults with Crohn’s disease [see Use in Specific Populations (8.4), Clinical Pharmacology (12.2)]. Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression during treatment with budesonide.

 Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure of oral budesonide. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider reducing the dosage in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Corticosteroids, including budesonide, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic corticosteroid is recommended.

Monitor patients who are transferred from corticosteroid treatment with high systemic effects to corticosteroids with lower systemic availability, such as budesonide, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal axis suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of corticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic corticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Corticosteroids, including budesonide, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor patients for the development of infection and consider discontinuation of budesonide if the patient develops an infection while on treatment.

Tuberculosis

If budesonide is used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged budesonide therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune pediatric and adult patients taking corticosteroids, including budesonide. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including budesonide. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with budesonide. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including budesonide, may exacerbate systemic fungal infections; therefore, avoid budesonide use in the presence of such infections. For patients on chronic budesonide therapy who develop systemic fungal infections, budesonide withdrawal or dosage reduction is recommended.

Amebiasis

Corticosteroids, including budesonide, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating budesonide in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Avoid budesonide in patients with known or suspected Strongyloides (threadworm) infection. Corticosteroid-induced immunosuppression may lead to Strongyloides superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Cerebral Malaria

Avoid corticosteroids, including budesonide, in patients with cerebral malaria.

Ocular Herpes Simplex

Avoid corticosteroids, including budesonide, in patients with active ocular herpes simplex.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where corticosteroids may have unwanted effects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adults

The data described below reflect exposure to budesonide in 520 patients with Crohn’s disease, including 520 exposed to 9 mg per day (total daily dose) for 8 weeks and 145 exposed to 6 mg per day for one year in placebo controlled clinical trials. Of the 520 patients, 38% were males and the age range was 17 to 74 years.

Treatment of Mild to Moderate Active Crohn’s Disease

The safety of budesonide was evaluated in 651 adult patients in five clinical trials of 8 weeks duration in patients with active mild to moderate Crohn’s disease. The most common adverse reactions, occurring in greater than or equal to 5% of the patients, are listed in Table 1.

Table 1: Common Adverse Reactions1 in 8-Week Treatment Clinical Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <br/> <br/> <br/> <br/> <p class="First"> <span class="Bold">Adverse Reaction </span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide<br/> 9 mg </span> </p> <p> <span class="Bold">n = 520</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">n = 107</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Prednisolone<span class="Sup">2</span> <br/> 40 mg </span> </p> <p> <span class="Bold">n = 145</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Comparator<span class="Sup">3</span></span> </p> <p> <span class="Bold">n = 88</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Headache</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">107 (21)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">19 (18)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31 (21)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11 (13)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Respiratory Infection </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">55 (11)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">20 (14)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Nausea</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">57 (11)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10 (9)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18 (12)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">7 (8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Back Pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">36 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10 (9)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17 (12)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dyspepsia</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (4)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17 (12)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Dizziness </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">38 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18 (12)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Abdominal Pain</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">32 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">18 (17)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (4)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">10 (11)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Flatulence</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">30 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12 (8)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Vomiting</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">29 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (4)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Fatigue </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">25 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">11 (8)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0 (0)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Pain </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">24 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">8 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">17 (12)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="5"> <p class="First"> <span class="Sup">1</span> Occurring in greater than or equal to 5% of the patients in any treated group.<br/> <span class="Sup">2</span> Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg per week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg per week.<br/> <span class="Sup">3</span> This drug is not approved for the treatment of Crohn’s disease in the United States.</p> </td> </tr> </tbody> </table></div>

The incidence of signs and symptoms of hypercorticism reported by active questioning of patients in 4 of the 5 short-term clinical trials are displayed in Table 2.

Table 2: Summary and Incidence of Signs/Symptoms of Hypercorticism in 8-Week Treatment Clinical Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <br/> <br/> <br/> <br/> <p class="First"> <span class="Bold">Signs/Symptom</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide<br/> 9 mg </span> </p> <p> <span class="Bold">n = 427</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">n = 107</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Prednisolone<span class="Sup">1</span> <br/> 40 mg </span> </p> <p> <span class="Bold">n = 145</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Total</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">145 (34%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">29 (27%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">69 (48%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Acne</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">63 (15)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14 (13)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">33 (23)<span class="Sup">2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Bruising Easily</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">63 (15)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">12 (11)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Moon Face</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">46 (11)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (4)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">53 (37)<span class="Sup">2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Swollen Ankles</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">32 (7)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (6)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13 (9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Hirsutism<span class="Sup">3</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">22 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Buffalo Hump</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (1)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Skin Striae</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (1)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0 (0)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="4"> <p class="First"> <span class="Sup">1</span> Prednisolone tapering scheme: either 40 mg in week 1 to 2, thereafter tapering with 5 mg/week; or 40 mg in week 1 to 2, 30 mg in week 3 to 4, thereafter tapering with 5 mg/week. </p> <p> <span class="Sup">2</span> Statistically significantly different from budesonide 9 mg.</p> <p> <span class="Sup">3</span> Including hair growth increased, local and hair growth increased, general.</p> </td> </tr> </tbody> </table></div>

Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease

The safety of budesonide was evaluated in 233 adult patients in four long-term clinical trials (52 weeks) of maintenance of clinical remission in patients with mild to moderate Crohn’s disease. A total of 145 patients were treated with budesonide 6 mg once daily.

The adverse reaction profile of budesonide 6 mg once daily in maintenance of Crohn’s disease was similar to that of short-term treatment with budesonide 9 mg once daily in active Crohn’s disease. In the long-term clinical trials, the following adverse reactions occurred in greater than or equal to 5% and are not listed in Table 1: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).

Signs/symptoms of hypercorticism reported by active questioning of patients in the long-term maintenance clinical trials are displayed in Table 3.

Table 3: Summary and Incidence of Signs/Symptoms of Hypercorticism in Long-Term Clinical Trials

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <col width="17pt"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <br/> <br/> <br/> <br/> <p class="First"> <span class="Bold">Signs/Symptom</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide<br/> 3 mg </span> </p> <p> <span class="Bold">n = 88</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide<br/> 6 mg </span> </p> <p> <span class="Bold">n = 145</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo </span> </p> <p> <span class="Bold">n = 143</span> </p> <p> <span class="Bold">Number (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Bruising Easily</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">15 (10)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Acne</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">4 (5)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">14 (10)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Moon Face</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (3)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6 (4)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Hirsutism</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">5 (3)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 (1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Swollen Ankles</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">3 (2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Buffalo Hump</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 (1)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">1 (1)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule"> <p class="First">Skin Striae</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">2 (2)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

The incidence of signs/symptoms of hypercorticism as described above in long-term maintenance clinical trials was similar to that seen in the short-term treatment clinical trials.

Less Common Adverse Reactions in Treatment and Maintenance Clinical Trials

Less common adverse reactions (less than 5%), occurring in adult patients treated with budesonide 9 mg (total daily dose) in short-term treatment clinical studies and/or budesonide 6 mg (total daily dose) in long-term maintenance clinical trials, with an incidence are listed below by system organ class:

Cardiac disorders: palpitation, tachycardia

Eye disorders: eye abnormality, vision abnormal

General disorders and administration site conditions: asthenia, chest pain, dependent edema, face edema, flu-like disorder, malaise, fever

Gastrointestinal disorders: anus disorder, enteritis, epigastric pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema, tooth disorder

Infections and infestations: Ear infection - not otherwise specified, bronchitis, abscess, rhinitis, urinary tract infection, thrush

Investigations: weight increased

Metabolism and nutrition disorders: appetite increased

Musculoskeletal and connective tissue disorders: arthritis, cramps, myalgia

Nervous system disorders: hyperkinesia, paresthesia, tremor, vertigo, somnolence, amnesia

Psychiatric disorders: agitation, confusion, insomnia, nervousness, sleep disorder

Renal and urinary disorders: dysuria, micturition frequency, nocturia

Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder

Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder

Skin and subcutaneous tissue disorders: alopecia, dermatitis, eczema, skin disorder, sweating increased, purpura

Vascular disorders: flushing, hypertension

Bone Mineral Density

A randomized, open, parallel-group multicenter safety clinical trial specifically compared the effect of budesonide (less than 9 mg per day) and prednisolone (less than 40 mg per day) on bone mineral density over 2 years when used at doses adjusted to disease severity. Bone mineral density decreased significantly less with budesonide than with prednisolone in steroid-naïve patients, whereas no difference could be detected between treatment groups for steroid-dependent patients and previous steroid users. The incidence of symptoms associated with hypercorticism was significantly higher with prednisolone treatment.

Clinical Laboratory Test Findings

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to budesonide, were reported in greater than or equal to 1% of patients: hypokalemia, leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate increased, alkaline phosphatase increased, atypical neutrophils, c-reactive protein increased and adrenal insufficiency.

Pediatrics - Treatment of Mild to Moderate Active Crohn’s Disease

Adverse reactions reported in pediatric patients 8 to 17 years of age, who weigh more than 25 kg, were similar to those reactions described above in adult patients.

The following adverse reactions have been reported during post-approval use of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Anaphylactic reactions Nervous System Disorders: Benign intracranial hypertension Psychiatric Disorders: Mood swings

Budesonide is a substrate for CYP3A4. Avoid use with CYP3A4 inhibitors. Concomitant oral administration of a strong CYP3A4 inhibitor (ketoconazole) caused an eight-fold increase of the systemic exposure to oral budesonide. Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and cyclosporine) can increase systemic budesonide concentrations [see Clinical Pharmacology (12.3)].

Grapefruit Juice

Avoid ingestion of grapefruit juice with budesonide. Intake of grapefruit juice which inhibits CYP3A4 activity with budesonide can increase the systemic exposure for budesonide [see Clinical Pharmacology (12.3)].

Risk Summary

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations [see Clinical Considerations]. In animal reproduction studies with pregnant rats and rabbits, administration of subcutaneous budesonide during organogenesis at doses approximately 0.5 times or 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 

Disease-Associated Maternal and/or Embryo/Fetal Risk 

Some published epidemiological studies show an association of adverse pregnancy outcomes in women with Crohn’s disease, including preterm birth and low birth weight infants, during periods of increased disease activity (including increased stool frequency and abdominal pain). Pregnant women with Crohn’s disease should be counseled regarding the importance of controlling disease. 

Fetal/Neonatal adverse reactions 

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)].

Animal Data 

Budesonide was teratogenic and embryolethal in rabbits and rats. 

In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6 to 15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). 

In a peri- and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Risk Summary

Lactation studies have not been conducted with oral budesonide, including budesonide, and no information is available on the effects of the drug on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide and any potential adverse effects on the breastfed infant from budesonide, or from the underlying maternal condition.

One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide is higher (up to 9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study. 

The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 2.15 ng/mL to 4.31 ng/mL which is up to 10 times higher than the 0.43 ng/mL to 0.86 ng/mL for a 800 mcg daily dose of inhaled budesonide at steady-state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.

The safety and effectiveness of budesonide have been established in pediatric patients 8 to 17 years of age who weigh more than 25 kg for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon. Use of budesonide in this age group is supported by evidence from adequate and well controlled studies of budesonide in adults, with additional data from 2 clinical studies in 149 pediatric patients treated up to 8 weeks and one pharmacokinetic study in 8 pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. 

The observed safety profile of budesonide in pediatric patients is consistent with its known safety profile in adults and no new safety concerns were identified [see Adverse Reactions (6.1)]. 

The safety and effectiveness of budesonide have not been established in pediatric patients less than 8 years of age for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon. 

The safety and effectiveness of budesonide have not been established in pediatric patients for the maintenance of clinical remission of mild to moderate Crohn’s disease. An open-label study to evaluate the safety and tolerability of budesonide as maintenance treatment in pediatric patients aged 5 to 17 years was conducted, and did not establish the safety and efficacy of maintenance of clinical remission.

Systemic corticosteroids, including budesonide, may cause a reduction of growth velocity in pediatric patients. Pediatric patients with Crohn’s disease have a 17% higher mean systemic exposure and cortisol suppression than adults with Crohn’s disease [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)]. 

Clinical studies of budesonide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 651 patients treated with budesonide in clinical studies, 17 (3%) were greater than or equal to 65 years of age and none were greater than 74 years of age. Other reported clinical experience has not identified differences in responses between the elderly and 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.

Patients with moderate to severe hepatic impairment (Child-Pugh Class B and C, respectively) could be at an increased risk of hypercorticism and adrenal axis suppression due to an increased systemic exposure to budesonide [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. Avoid use in patients with severe hepatic impairment (Child-Pugh Class C). Monitor for increased signs and/or symptoms of hypercorticism and consider dosage reduction in patients with moderate hepatic impairment (Child-Pugh Class B) [see Dosage and Administration (2.4)]. No dosage adjustment is needed in patients with mild hepatic impairment (Child-Pugh Class A).

Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.

{ "type": "p", "children": [], "text": "Reports of acute toxicity and/or death following overdosage of glucocorticoids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. " }

If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily.

{ "type": "p", "children": [], "text": "If corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism and adrenal axis suppression may occur. For chronic overdosage in the case of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. " }

Single oral doses of 200 mg/kg and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

{ "type": "p", "children": [], "text": "Single oral doses of 200 mg/kg and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. " }

Budesonide USP, the active ingredient of budesonide delayed-release capsules, is a synthetic corticosteroid. Budesonide, USP is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide, USP is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide, USP is C25H34O6 and its molecular weight is 430.5 g/mol. Its structural formula is:

{ "type": "p", "children": [], "text": "Budesonide USP, the active ingredient of budesonide delayed-release capsules, is a synthetic corticosteroid. Budesonide, USP is designated chemically as (RS)-11β, 16α, 17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide, USP is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide, USP is C25H34O6 and its molecular weight is 430.5 g/mol. Its structural formula is:" }

Budesonide, USP is a white to off-white crystalline powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in methylene chloride. Its partition coefficient between octanol and water at pH 5 is 1.6 x 103 ionic strength 0.01.

{ "type": "p", "children": [], "text": "Budesonide, USP is a white to off-white crystalline powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in methylene chloride. Its partition coefficient between octanol and water at pH 5 is 1.6 x 103 ionic strength 0.01. " }

Each delayed-release capsule for oral administration contains 3 mg of micronized budesonide, USP with the following inactive ingredients: cetyl alcohol, corn starch, ethyl cellulose, hypromellose, macrogol, methacrylic acid copolymer type C, sodium lauryl sulfate, sugar, talc and triethyl citrate. The capsule shells have the following inactive ingredients: D&C yellow #10, FD&C blue #1, FD&C red #40, FD&C yellow #6, gelatin and titanium dioxide. The monogramming ink has the following inactive ingredients: D&C yellow #10, ethanol, FD&C blue #1, FD&C blue #2, FD&C red #40, iron oxide black, methanol, N-butyl alcohol, propylene glycol and shellac.

{ "type": "p", "children": [], "text": " Each delayed-release capsule for oral administration contains 3 mg of micronized budesonide, USP with the following inactive ingredients: cetyl alcohol, corn starch, ethyl cellulose, hypromellose, macrogol, methacrylic acid copolymer type C, sodium lauryl sulfate, sugar, talc and triethyl citrate. The capsule shells have the following inactive ingredients: D&C yellow #10, FD&C blue #1, FD&C red #40, FD&C yellow #6, gelatin and titanium dioxide. The monogramming ink has the following inactive ingredients: D&C yellow #10, ethanol, FD&C blue #1, FD&C blue #2, FD&C red #40, iron oxide black, methanol, N-butyl alcohol, propylene glycol and shellac." }

Budesonide is an anti-inflammatory corticosteroid and has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to glucocorticoid receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

Treatment with glucocorticoids, including budesonide, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. There was a positive correlation between the percent (%) reduction of AUC0-24 of plasma cortisol and systemic exposure to budesonide both in pediatric and adult patients.

Adults

Plasma cortisol suppression was compared following five days’ administration of budesonide and prednisolone in a crossover study in healthy volunteers. The mean decrease in the area under the plasma cortisol concentration-time curve over 24 hour (AUC0-24) was greater (78%) with prednisolone 20 mg per day compared to 45% with budesonide 9 mg per day. 

Pediatrics

The effect of budesonide on endogenous cortisol concentrations was compared between pediatrics (n = 8, aged 9 to 14 years) and adults (n = 6) with active Crohn’s disease following administration of budesonide 9 mg once daily for 7 days. Compared to baseline values before treatment, the mean decrease in the AUC0-24 of cortisol was 64% (± 18%) in pediatrics and 50% (± 27%) in adults after budesonide treatment [see Warnings and Precautions (5.1), Adverse Reactions (6.1) and Use in Specific Populations (8.4)]. 

The responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) was studied in pediatric patients aged 8 to 17 years, with mild to moderate active Crohn’s disease in randomized, double-blind, active control study [see Clinical Studies (14.1)]. After 8 weeks of treatment with 9 mg once daily budesonide or with prednisolone, administered at tapering doses starting from 1 mg/kg, the proportion of patients with normal response to the ACTH challenge was 6% in the budesonide group compared to none in the prednisolone group; the proportion of patients with morning p-cortisol of greater than 5 mcg/dL was 50% in the budesonide group compared to 22% in the prednisolone group. The mean morning p-cortisol was 6.3 mcg/dL in the budesonide group and 2.6 mcg/dL in the prednisolone group (Table 4).

Table 4: Proportion of Pediatric Patients 8 to 17 years old with Peak Endogenous Cortisol Levels (above 18 mcg/dL) after ACTH Stimulation and Normal Response* to ACTH Challenge Following Administration of Budesonide or Prednisolone for 8 weeks

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="17px"/> <col width="17px"/> <col width="17px"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Budesonide</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">Prednisolone</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First">Peak plasma cortisol above 18 mcg/dL</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">At baseline</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">91% (20/22)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">91% (21/23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">At week 8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">25% (4/16)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0% (0/18)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First">Normal response<span class="Sup">*</span> to ACTH challenge</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">At baseline</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">73% (16/22)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">78% (18/23)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">At week 8</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">6% (1/16)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">0% (0/18)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="3"> <p class="First"> <span class="Sup">*</span>The normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level above 5 mcg/dL; 2) increase in cortisol level by at least 7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of above 18 mcg/dL following ACTH challenge. Cortisol concentration was measured at 30 min after intravenous or intramuscular injection of 0.25 mg cosyntropin at baseline and at week 8 after treatment.</p> </td> </tr> </tbody> </table></div>

Absorption

Mean oral bioavailability of budesonide ranged from 9% to 21% both in patients and in healthy subjects, demonstrating a high first-pass elimination of the drug. 

Budesonide pharmacokinetics were dose-proportional following repeated administration in the dose range of 3 mg to 15 mg. No accumulation of budesonide was observed following repeated dosing. 

Following oral administration of a single dose of 9 mg budesonide in healthy subjects under fasting condition, the mean peak plasma concentration (Cmax) and the area under the plasma concentration time curve (AUC) for budesonide were 1.50 ± 0.79 ng/mL and 14.13 ± 7.33 ng•hr/mL, respectively. The time to peak concentration (Tmax) varied between 2 and 8 hours with a median value of 3.5 hours. In a different study, following oral administration of 9 mg budesonide for five days in healthy subjects, the mean Cmax and the steady state AUC for budesonide were 2.28 ± 0.77 ng/mL and 15.93 ± 6.29 ng•hr/mL, respectively.

Following administration of 9 mg budesonide once daily in patients with active Crohn’s disease, the mean Cmax and AUC were 1.7 ± 0.9 ng/mL and 15.1 ± 8.5 ng•hr/mL, respectively. Following administration of budesonide, the Tmax ranged in individual patients from 0.5 to 10 hours.

Concomitant administration of a high-fat meal delayed the Tmax of budesonide by 2.3 hours compared to that under fasted conditions but did not significantly affect the AUC in healthy subjects. The mean Cmax and AUC of budesonide were similar when single dose of budesonide (9 mg) was administered after opening the capsules and sprinkling the granules on applesauce versus as intact capsules in the fasted state (N = 24) in healthy subjects. The Tmax ranged from 3 to 10 hours with a median of 4 hours after administration of sprinkled granules on applesauce.

Distribution

The mean volume of distribution (Vss) of budesonide varied between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding was estimated to be 85% to 90% in the concentration range 0.43 ng/mL to 99.02 ng/mL, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations was about 0.8. 

Elimination

Budesonide had a plasma clearance, 0.9 L/min to 1.8 L/min in healthy adults. Mean plasma clearance after intravenous administration of budesonide in patients with Crohn’s disease was 1.0 L/min. These plasma clearance values approached the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug. The plasma elimination half-life after administration of intravenous doses ranged between 2 and 3.6 hours, and did not differ between healthy adults and patients with Crohn’s disease. The mean ± SD plasma elimination half-life after a single dose of budesonide (9 mg) in the fasted state (N = 24) in healthy subjects was 6.3 ± 1.6 hours and ranged between 2 and 8 hours.

Metabolism

Following absorption, budesonide is subject to high first pass metabolism (80% to 90%). In vitro experiments in human liver microsomes demonstrated that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The corticosteroid activity of these metabolites was negligible (less than 1/100) in relation to that of the parent compound. In vivo investigations with intravenous doses in healthy subjects were in agreement with the in vitro findings.

Excretion

Budesonide was excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity was found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide was detected in urine. 

Specific Populations

Age: Pediatric Population (8 years and older) 

The pharmacokinetics of budesonide were investigated in pediatric patients aged 9 to 14 years (n = 8) after oral administration of budesonide and intravenous administration of budesonide. Following administration of 9 mg budesonide once daily for 7 days, the median time to peak plasma concentration of budesonide was 5 hours and the mean peak plasma concentration was 2.58 ± 1.51 ng/mL. The mean AUC was 17.78 ± 5.25 ng•hr/mL and 17% higher than that in adult patients with Crohn’s disease in the same study. The mean absolute oral availability was 9.2% (3% to 17%; n = 4) in pediatric patients. 

After single dose administration of intravenous budesonide (n = 4), the mean volume of distribution (Vss) was 2.2 ± 0.4 L/kg and mean clearance was 0.81 ± 0.2 L/min. The mean elimination half-life was 1.9 hours in pediatric patients. The body-weight normalized clearance in pediatric patients was 20.5 mL/min/kg in comparison to 15.9 mL/min/kg in adult patients after intravenous administration [see Warnings and Precautions (5.1), Use in Specific Population (8.4)].

Hepatic Impairment 

In patients with mild (Child-Pugh Class A, n = 4) or moderate (Child-Pugh Class B, n = 4) hepatic impairment, budesonide 4 mg was administered orally as a single dose. The patients with moderate hepatic impairment had a 3.5-fold higher AUC compared to the healthy subjects with normal hepatic function while the patients with mild hepatic impairment had an approximately 1.4-fold higher AUC. The Cmax values demonstrated similar increases [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. The increased systemic exposure in patients with mild hepatic impairment was not considered to be clinically relevant. Patients with severe liver impairment (Child-Pugh Class C) were not studied.

Drug Interaction Studies

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide several-fold. Conversely, induction of CYP3A4 potentially could result in the lowering of budesonide plasma concentrations. 

Effects of Other Drugs on Budesonide 

Ketoconazole 

In an open, non-randomized, cross-over study, 6 healthy subjects were given budesonide 10 mg as a single dose, either alone or concomitantly with the last ketoconazole dose of 3 days treatment with ketoconazole 100 mg twice daily. Co-administration of ketoconazole resulted in an eight-fold increase in AUC of budesonide, compared to budesonide alone [see Drug Interactions (7.1)]. 

Grapefruit Juice 

In an open, randomized, cross-over study, 8 healthy subjects were given budesonide 3 mg, either alone, or concomitantly with 600 mL concentrated grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), on the last of 4 daily administrations. Concomitant administration of grapefruit juice resulted in a 2-fold increase of the bioavailability of budesonide compared to budesonide alone [see Drug Interactions (7.1)]. 

Oral Contraceptives (CYP3A4 Substrates) 

In a parallel study, the pharmacokinetics of budesonide were not significantly different between healthy female subjects who received oral contraceptives containing desogestrel 0.15 mg and ethinyl estradiol 30 mcg and healthy female subjects who did not receive oral contraceptives. Budesonide 4.5 mg once daily (one-half the recommended dose) for one week did not affect the plasma concentrations of ethinyl estradiol, a CYP3A4 substrate. The effect of budesonide 9 mg once daily on the plasma concentrations of ethinyl estradiol was not studied. 

Omeprazole 

In a study in 11 healthy subjects, performed in a double-blind, randomized, placebo controlled manner, the effect of 5 to 6 days treatment with omeprazole 20 mg once daily on the pharmacokinetics of budesonide administered as budesonide 9 mg as a single dose was investigated. Omeprazole 20 mg once daily did not affect the absorption or pharmacokinetics of budesonide. 

Cimetidine 

In an open, non-randomized, cross-over study, the potential effect of cimetidine on the pharmacokinetics of budesonide was studied. Six healthy subjects received cimetidine 1 gram daily (200 mg with meals and 400 mg at night) for 2 separate 3-day periods. Budesonide 4 mg was administered either alone or on the last day of one of the cimetidine treatment periods. Co-administration of cimetidine resulted in a 52% and 31% increase in the budesonide peak plasma concentration and the AUC of budesonide, respectively.

Carcinogenicity studies with budesonide were conducted in rats and mice. 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 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis).

Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK +/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

Adults

The efficacy of budesonide were evaluated in 994 patients with mild to moderate active Crohn’s disease of the ileum and/or ascending colon in 5 randomized and double-blind studies of 8 weeks duration. The study patients ranged in age from 17 to 85 (mean 35), 40% were male and 97% were white. The Crohn’s Disease Activity Index (CDAI) was the main clinical assessment used for determining efficacy in these 5 studies.1 The CDAI is a validated index based on subjective aspects rated by the patient (frequency of liquid or very soft stools, abdominal pain rating and general well-being) and objective observations (number of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal mass, body weight and hematocrit). Clinical improvement, defined as a CDAI score of less than or equal to 150 assessed after 8 weeks of treatment, was the primary efficacy variable in these 5 comparative efficacy studies of budesonide. Safety assessments in these studies included monitoring of adverse reactions. A checklist of potential symptoms of hypercorticism was used. 

One study (Study 1) compared the efficacy of budesonide 9 mg daily in the morning to a comparator. At baseline, the median CDAI was 272. Budesonide 9 mg daily resulted in a significantly higher clinical improvement rate at Week 8 than the comparator. See Table 5.

Table 5: Clinical Improvement Rates (CDAI less than or equal to 150) After 8 weeks of Treatment

<div class="scrollingtable"><table border="1" cellpadding="0" cellspacing="0" width="100%"> <col width="11.54%"/> <col width="20.1%"/> <col width="20.1%"/> <col width="17.48%"/> <col width="14.1%"/> <col width="16.68%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Clinical <br/> Study</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide</span> </p> <p> <span class="Bold">9 mg Daily</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Budesonide</span> </p> <p> <span class="Bold">4.5 mg Twice Daily</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Comparator<span class="Sup">3</span></span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Placebo</span> </p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First"> <span class="Bold">Prednisolone</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">1</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">62/91 (69%)<span class="Sup">1</span> </p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">37/83 (45%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">2</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">31/61 (51%)<span class="Sup">2</span> </p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13/64 (20%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">3</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">38/79 (48%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">41/78 (53%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">13/40 (33%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">4</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">35/58 (60%)</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">25/60 (42%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">35/58 (60%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule"> <p class="First">5</p> </td><td class="Botrule Lrule Rrule Toprule"> <p class="First">45/86 (52%)</p> </td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"></td><td class="Botrule Lrule Rrule Toprule"> <p class="First">56/85 (65%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="6"> <p class="First"> <span class="Sup">1</span> p = 0.0004 compared to comparator.</p> <p> <span class="Sup">2</span> p = 0.001 compared to placebo.</p> <p> <span class="Sup">3</span> This drug is not approved for the treatment of Crohn’s disease in the United States.</p> </td> </tr> </tbody> </table></div>

Two placebo-controlled clinical trials (Studies 2 and 3) were conducted. Study 2 involved 258 patients and tested the effects of graded doses of budesonide (1.5 mg twice daily, 4.5 mg twice daily, or 7.5 mg twice daily) versus placebo. At baseline, the median CDAI was 290. The 1.5 mg twice daily arm (data not shown) could not be differentiated from placebo. The 4.5 mg twice daily arm was statistically different from placebo (Table 5), while no additional benefit was seen when the daily budesonide dose was increased to 15 mg per day (data not shown). Study 3 was a 3-armed parallel group study. The groups were treated with budesonide 9 mg once daily, budesonide 4.5 mg twice daily and placebo for 8 weeks, followed by a 2-week double-blind taper phase. The median CDAI at baseline was 263. Neither 9 mg daily nor 4.5 mg twice daily budesonide dose levels were statistically different from placebo (Table 5). The recommended dosage of budesonide for the treatment of mild to moderate active Crohn’s disease involving the ileum and/or the ascending colon in adults is 9 mg once daily in the morning for up to 8 weeks [see Dosage and Administration (2.1)].

Two clinical trials (Studies 4 and 5) compared budesonide with oral prednisolone (initial dose 40 mg per day). Study 4 was a 3-armed parallel group study. The groups were treated with budesonide 9 mg once daily, budesonide 4.5 mg twice daily and prednisolone 40 mg (tapered dose) for 8 weeks, followed by a 4-week double blind taper phase. At baseline, the median CDAI was 277. Equal clinical improvement rates (60%) were seen in the budesonide 9 mg daily and the prednisolone groups in Study 4. In Study 5, 13% fewer patients in the budesonide group experienced clinical improvement than in the prednisolone group (no statistical difference) (Table 5). The proportion of patients with normal plasma cortisol values (greater than 64.58 ng/mL) was significantly higher in the budesonide groups in both trials (60% to 66%) than in the prednisolone groups (26% to 28%) at Week 8. 

Pediatrics (8 to 17 Years of Age)

The effectiveness of budesonide, in pediatric patients aged 8 to 17 years, who weigh more than 25 kg with mild to moderate active Crohn’s disease (defined as Crohn's Disease Activity Index (CDAI) ≥ 200) involving the ileum and/or the ascending colon, was assessed in one randomized, double-blind, active control study. This study compared budesonide 9 mg once daily, with prednisolone, administered at tapering doses starting from 1 mg/kg. Twenty-two (22) patients were treated with budesonide delayed-release capsules and 24 patients were treated with prednisolone. After 8 weeks of treatment, 55% (95% CI: 32%, 77%) of patients treated with budesonide reached the endpoint (CDAI ≤ 150), as compared to 68% (95% CI: 47%, 89%) of patients treated with prednisolone. The average number of liquid or very soft stools per day (assessed over 7 days) decreased from 1.49 at baseline to 0.96 after treatment with budesonide and 2.00 at baseline to 0.52 after treatment with prednisolone. The average daily abdominal pain rating (where 0 = none, 1 = mild, 2 = moderate, and 3 = severe) decreased from 1.49 at baseline to 0.54 after treatment with budesonide and 1.64 at baseline to 0.38 after 8 weeks of treatment with prednisolone. 

Use of budesonide in this age group is supported by evidence from adequate and well-controlled studies of budesonide in adults, and by safety and pharmacokinetic studies performed in pediatric patients.

Adults

The efficacy of budesonide for maintenance of clinical remission were evaluated in four double-blind, placebo-controlled, 12-month trials in which 380 patients were randomized and treated once daily with 3 mg or 6 mg budesonide or placebo. Patients ranged in age from 18 to 73 (mean 37) years. Sixty percent of the patients were female and 99% were Caucasian. The mean CDAI at entry was 96. Among the four clinical trials, approximately 75% of the patients enrolled had exclusively ileal disease. Colonoscopy was not performed following treatment. Budesonide 6 mg per day prolonged the time to relapse, defined as an increase in CDAI of at least 60 units to a total score greater than 150 or withdrawal due to disease deterioration. The median time to relapse in the pooled population of the 4 studies was 154 days for patients taking placebo, and 268 days for patients taking budesonide 6 mg per day. Budesonide 6 mg per day reduced the proportion of patients with loss of symptom control relative to placebo in the pooled population for the 4 studies at 3 months (28% versus 45% for placebo).

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s Disease Activity Index, National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70(3): 439-444.

{ "type": "p", "children": [], "text": "1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s Disease Activity Index, National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70(3): 439-444." }

Budesonide delayed-release capsules, 3 mg, are supplied as hard gelatin capsules with an opaque light gray body imprinted “778” and an opaque maroon cap imprinted “AMNEAL” with black ink.

{ "type": "p", "children": [], "text": "Budesonide delayed-release capsules, 3 mg, are supplied as hard gelatin capsules with an opaque light gray body imprinted “778” and an opaque maroon cap imprinted “AMNEAL” with black ink." }

They are available as follows:

{ "type": "p", "children": [], "text": "They are available as follows: " }

Bottles of 100:                        NDC 53746-778-10

{ "type": "p", "children": [], "text": "Bottles of 100:                        NDC 53746-778-10" }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. " }

Keep container tightly closed.

{ "type": "p", "children": [], "text": "Keep container tightly closed. " }

Advise Patients to read the FDA-Approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise Patients to read the FDA-Approved patient labeling (Patient Information). " }

Hypercorticism and Adrenal Axis Suppression

{ "type": "p", "children": [], "text": "\nHypercorticism and Adrenal Axis Suppression \n" }

Advise patients that budesonide may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide from systemic corticosteroids [see Warnings and Precautions (5.1, 5.2)]. Advise patients that replacement of systemic corticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

{ "type": "p", "children": [], "text": "Advise patients that budesonide may cause hypercorticism and adrenal axis suppression and to follow a taper schedule, as instructed by their healthcare provider if transferring to budesonide from systemic corticosteroids [see Warnings and Precautions (5.1, 5.2)]. Advise patients that replacement of systemic corticosteroids with budesonide may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug." }

Immunosuppression and Increased Risk of Infection

{ "type": "p", "children": [], "text": "\nImmunosuppression and Increased Risk of Infection\n" }

Advise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients inform their healthcare provider if they are exposed to varicella or measles or if they develop a new or worsening infection [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients inform their healthcare provider if they are exposed to varicella or measles or if they develop a new or worsening infection [see Warnings and Precautions (5.3)]." }

Kaposi’s Sarcoma

{ "type": "p", "children": [], "text": "\nKaposi’s Sarcoma \n" }

Advise patients that Kaposi’s sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi’s sarcoma [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "Advise patients that Kaposi’s sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi’s sarcoma [see Warnings and Precautions (5.4)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy \n" }

Advise female patients that budesonide may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise female patients that budesonide may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

Administration

{ "type": "p", "children": [], "text": "\nAdministration\n" }

{ "type": "ul", "children": [ "Take budesonide once daily in the morning. ", "Swallow budesonide delayed-release capsules whole. Do not chew or crush. ", "For patients unable to swallow an intact capsule, budesonide delayed-release capsules can be opened and administered as follows:\n \nPlace one tablespoonful of applesauce into a clean container (e.g., empty bowl). The applesauce used should not be hot and should be soft enough to be swallowed without chewing. \nOpen the capsule(s). \nCarefully empty all the granules inside the capsule(s) on the applesauce. \nMix the granules with the applesauce. \nConsume the entire contents within 30 minutes of mixing. Do not chew or crush the granules. Do not save the applesauce and granules for future use. \nFollow the applesauce and granules immediately with a glass (8 ounces) of cool water to ensure complete swallowing of the granules. \n\n", "Avoid consumption of grapefruit juice for the duration of their budesonide therapy [see Drug Interactions (7.1)]. " ], "text": "" }

Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Ahmedabad 382220, INDIA

{ "type": "p", "children": [], "text": "Manufactured by:\nAmneal Pharmaceuticals Pvt. Ltd.\nAhmedabad 382220, INDIA" }

Distributed by:  Amneal Pharmaceuticals LLC  Bridgewater, NJ 08807

{ "type": "p", "children": [], "text": "Distributed by: \nAmneal Pharmaceuticals LLC \nBridgewater, NJ 08807" }

Rev. 06-2025-01

{ "type": "p", "children": [], "text": "Rev. 06-2025-01" }

Dispense with Patient Information available at: documents.amneal.com/mg/ppi-budesonide-dr-cap.pdf

{ "type": "p", "children": [], "text": "Dispense with Patient Information available at:\ndocuments.amneal.com/mg/ppi-budesonide-dr-cap.pdf" }

<div class="scrollingtable"><table cellpadding="0" cellspacing="0" width="100%"> <col width="17px"/> <col/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Budesonide (bue des’ oh nide) Delayed-Release Capsules</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First">Read this Patient Information before you start taking budesonide delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">What are budesonide delayed-release capsules?</span> </p> <p>Budesonide delayed-release capsules are a prescription corticosteroid medicine used to treat mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon):</p> <ul class="Disc"> <li>in people 8 years of age and older with active Crohn’s disease</li> <li>in adults to help keep symptoms from coming back for up to 3 months</li> </ul> <p>It is not known if budesonide delayed-release capsules are safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon).</p> <p>It is not known if budesonide delayed-release capsules are safe and effective in children to help keep symptoms of mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Who should not take budesonide delayed-release capsules?</span> </p> <p> <span class="Bold">Do not take budesonide delayed-release capsules if:</span> </p> <ul class="Disc"> <li>you are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for a complete list of ingredients in budesonide delayed-release capsules.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">Before you take budesonide delayed-release capsules tell your healthcare provider if you have any other medical conditions including if you:</span> </p> <ul class="Disc"> <li>have liver problems.</li> <li>are planning to have surgery.</li> <li>have chicken pox or measles or have recently been near anyone with chicken pox or measles.</li> <li>have an infection, including fungal and threadworm (Strongyloides) infections.</li> <li>have diabetes or glaucoma or have a family history of diabetes or glaucoma.</li> <li>have cataracts.</li> <li>have or had tuberculosis.</li> <li>have high blood pressure (hypertension).</li> <li>have decreased bone mineral density (osteoporosis).</li> <li>have stomach ulcers.</li> <li>have malaria of the brain (cerebral malaria).</li> <li>are pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide delayed-release capsules.</li> <li>are breastfeeding or plan to breastfeed. It is not known if budesonide passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide delayed-release capsules.</li> </ul> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide delayed-release capsules and other medicines may affect each other causing side effects.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">How should I take budesonide delayed-release capsules?</span> </p> <ul class="Disc"> <li>Take budesonide delayed-release capsules exactly as your healthcare provider tells you.</li> <li>Your healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed.</li> <li>Take budesonide delayed-release capsules 1 time each day in the morning.</li> <li>Take budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing.</li> <li>For patients, unable to swallow a whole capsule, budesonide delayed-release capsules can be opened and administered as follows: <ol class="Arabic"> <li>Place 1 tablespoonful of applesauce into a clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.</li> <li>Open the capsule. You may need to use more than 1 budesonide delayed-release capsule for the dose prescribed by your healthcare provider.</li> <li>Carefully empty all of the granules inside the capsule on the applesauce.</li> <li>Stir the granules with the applesauce.</li> <li>Swallow the applesauce and granules mixture within 30 minutes after preparing it. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to help with complete swallowing of the granules.</li> <li>Do not chew or crush the granules.</li> <li>Do not save the applesauce and granules for later use.</li> </ol> </li> <li>If you take too much budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room.</li> </ul> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">What should I avoid while taking budesonide delayed-release capsules?</span> </p> <ul class="Disc"> <li>Do not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood.</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">What are the possible side effects of budesonide delayed-release capsules?</span> </p> <p> <span class="Bold">Budesonide delayed-release capsules may cause serious side effects, including:</span> </p> <ul class="Disc"> <li> <span class="Bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism). </span>Long-time use of budesonide delayed-release capsules can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism:</li> </ul> </td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>acne</li> <li>bruise easily</li> <li>rounding of your face (moon face)</li> <li>ankle swelling</li> </ul> </td><td class="Rrule"> <ul class="Circle"> <li>thicker or more hair on your body and face</li> <li>a fatty pad or hump between your shoulders (buffalo hump)</li> <li>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul class="Disc"> <li> <span class="Bold">Adrenal suppression. </span>When budesonide delayed-release capsules are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide delayed-release capsules.</li> <li> <span class="Bold">Worsening of allergies. </span>If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules.</li> <li> <p class="First"> <span class="Bold">Decreased ability of your body to fight infections (immunosuppression) and i</span><span class="Bold">ncreased risk of infection. </span>Corticosteroid medicines, including budesonide delayed-release capsules, lower the ability of your immune system to fight infections and increase the risk of infections caused by virus, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines including budesonide delayed-release capsules can also:</p> <ul class="Circle"> <li>make current infections worse</li> <li>increase the risk of infections spreading (disseminated)</li> <li>increase the risk of making infections active again or making infections worse that have not been active (latent)</li> <li>hide (mask) some signs of infection</li> </ul> <p>These infections can be mild, but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide delayed-release capsules.</p> Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide delayed-release capsules, including flu-like symptoms such as:</li> </ul> </td> </tr> <tr> <td class="Lrule"> <ul class="Circle"> <li>fever</li> <li>chills</li> <li>stomach area (abdominal) pain</li> <li>aches</li> <li>diarrhea</li> </ul> </td><td class="Rrule"> <ul class="Circle"> <li>cough</li> <li>pain</li> <li>feeling tired</li> <li>nausea and vomiting</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <ul class="Circle"> <li>Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide delayed-release capsules your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide delayed-release capsules.</li> <li>Chicken pox and measles: People taking corticosteroid medicines, including budesonide delayed-release capsules, who have not had chicken pox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles.</li> <li>Hepatitis B Virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide delayed-release capsules. Your healthcare provider will test you for HBV before you start taking budesonide delayed-release capsules.</li> <li>Amebiasis: Inactive (latent) amebiasis before you start taking budesonide delayed-release capsules. Your healthcare provider should check you for amebiasis before you start taking budesonide delayed-release capsules in people who have spent time in the tropics or have unexplained diarrhea.</li> </ul> <ul class="Disc"> <li> <span class="Bold">Kaposi’s Sarcoma</span>. Kaposi’s sarcoma has happened in people who receive corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions.</li> </ul> <p class="First"> <span class="Bold">The most common side effects of budesonide delayed-release capsules in adults include:</span> </p> </td> </tr> <tr> <td class="Lrule"> <ul class="Disc"> <li>headache</li> <li>stomach area (abdominal) pain</li> <li>infection in your air passages (respiratory infection)</li> <li>gas</li> <li>nausea</li> </ul> </td><td class="Rrule"> <ul class="Disc"> <li>vomiting</li> <li>back pain</li> <li>tiredness</li> <li>indigestion</li> <li>pain</li> <li>dizziness</li> </ul> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2"> <p class="First"> <span class="Bold">The most common side effects of budesonide delayed-release capsules in children </span>8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults.</p> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of budesonide delayed-release capsules. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">How should I store budesonide delayed-release capsules?</span> </p> <ul class="Disc"> <li>Store budesonide delayed-release capsules at room temperature between 20° to 25°C (68° to 77°F).</li> <li>Keep budesonide delayed-release capsules in a tightly closed container.</li> </ul> <p> <span class="Bold">Keep budesonide delayed-release capsules and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">General information about the safe and effective use of budesonide delayed-release capsules.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide or Patient Information leaflet. Do not use budesonide delayed-release capsules for a condition for which it was not prescribed. Do not give budesonide delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about budesonide delayed-release capsules that is written for health professionals.</p> <p>For more information go to www.amneal.com or call 1-877-835-5472.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2"> <p class="First"> <span class="Bold">What are the ingredients in budesonide delayed-release capsules?</span> </p> <p> <span class="Bold">Active ingredient: </span>budesonide, USP</p> <p> <span class="Bold">Inactive ingredients: </span>cetyl alcohol, corn starch, ethyl cellulose, hypromellose, macrogol, methacrylic acid copolymer type C, sodium lauryl sulfate, sugar, talc and triethyl citrate.</p> <p>The capsule shell contains: D&amp;C yellow #10, FD&amp;C blue #1, FD&amp;C red #40, FD&amp;C yellow #6, gelatin and titanium dioxide.</p> <p>The monogramming ink contains: D&amp;C yellow #10, ethanol, FD&amp;C blue #1, FD&amp;C blue #2, FD&amp;C red #40, iron oxide black, methanol, N-butyl alcohol, propylene glycol and shellac.<br/> <br/>Manufactured by:<br/> <span class="Bold">Amneal Pharmaceuticals Pvt. Ltd.<br/> </span>Ahmedabad 382220, INDIA</p> <p>Distributed by:<br/> <span class="Bold">Amneal Pharmaceuticals LLC<br/> </span>Bridgewater, NJ 08807</p> <p>This Patient Information has been approved by the U.S. Food and Drug Administration.<br/> <br/> Rev. 06-2025-01</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table cellpadding=\"0\" cellspacing=\"0\" width=\"100%\">\n<col width=\"17px\"/>\n<col/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Budesonide (bue des’ oh nide) Delayed-Release Capsules</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">Read this Patient Information before you start taking budesonide delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are budesonide delayed-release capsules?</span>\n</p>\n<p>Budesonide delayed-release capsules are a prescription corticosteroid medicine used to treat mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon):</p>\n<ul class=\"Disc\">\n<li>in people 8 years of age and older with active Crohn’s disease</li>\n<li>in adults to help keep symptoms from coming back for up to 3 months</li>\n</ul>\n<p>It is not known if budesonide delayed-release capsules are safe and effective in children under 8 years of age, or in children 8 to 17 years of age who weigh 55 pounds (25 kg) or less, for the treatment of mild to moderate active Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon).</p>\n<p>It is not known if budesonide delayed-release capsules are safe and effective in children to help keep symptoms of mild to moderate Crohn’s disease that affects part of the small intestine (ileum) and part of the large intestine (ascending colon) from coming back.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take budesonide delayed-release capsules?</span>\n</p>\n<p>\n<span class=\"Bold\">Do not take budesonide delayed-release capsules if:</span>\n</p>\n<ul class=\"Disc\">\n<li>you are allergic to budesonide or any of the ingredients in budesonide delayed-release capsules. See the end of this leaflet for a complete list of ingredients in budesonide delayed-release capsules.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">Before you take budesonide delayed-release capsules tell your healthcare provider if you have any other medical conditions including if you:</span>\n</p>\n<ul class=\"Disc\">\n<li>have liver problems.</li>\n<li>are planning to have surgery.</li>\n<li>have chicken pox or measles or have recently been near anyone with chicken pox or measles.</li>\n<li>have an infection, including fungal and threadworm (Strongyloides) infections.</li>\n<li>have diabetes or glaucoma or have a family history of diabetes or glaucoma.</li>\n<li>have cataracts.</li>\n<li>have or had tuberculosis.</li>\n<li>have high blood pressure (hypertension).</li>\n<li>have decreased bone mineral density (osteoporosis).</li>\n<li>have stomach ulcers.</li>\n<li>have malaria of the brain (cerebral malaria).</li>\n<li>are pregnant or plan to become pregnant. Budesonide delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the possible risk to your unborn baby if you take budesonide delayed-release capsules when you are pregnant. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during your treatment with budesonide delayed-release capsules.</li>\n<li>are breastfeeding or plan to breastfeed. It is not known if budesonide passes into your breast milk or if it will affect your baby. Talk to your healthcare provider about the best way to feed your baby if you take budesonide delayed-release capsules.</li>\n</ul>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide delayed-release capsules and other medicines may affect each other causing side effects.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take budesonide delayed-release capsules?</span>\n</p>\n<ul class=\"Disc\">\n<li>Take budesonide delayed-release capsules exactly as your healthcare provider tells you.</li>\n<li>Your healthcare provider will tell you how many budesonide delayed-release capsules to take. Your healthcare provider may change your dose if needed.</li>\n<li>Take budesonide delayed-release capsules 1 time each day in the morning.</li>\n<li>Take budesonide delayed-release capsules whole. Do not chew or crush budesonide delayed-release capsules before swallowing.</li>\n<li>For patients, unable to swallow a whole capsule, budesonide delayed-release capsules can be opened and administered as follows:\n <ol class=\"Arabic\">\n<li>Place 1 tablespoonful of applesauce into a clean container, such as an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing.</li>\n<li>Open the capsule. You may need to use more than 1 budesonide delayed-release capsule for the dose prescribed by your healthcare provider.</li>\n<li>Carefully empty all of the granules inside the capsule on the applesauce.</li>\n<li>Stir the granules with the applesauce.</li>\n<li>Swallow the applesauce and granules mixture within 30 minutes after preparing it. Follow the applesauce and granules immediately with a glass (8 ounces) of cool water to help with complete swallowing of the granules.</li>\n<li>Do not chew or crush the granules.</li>\n<li>Do not save the applesauce and granules for later use.</li>\n</ol>\n</li>\n<li>If you take too much budesonide delayed-release capsules call your healthcare provider right away or go to the nearest hospital emergency room.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking budesonide delayed-release capsules?</span>\n</p>\n<ul class=\"Disc\">\n<li>Do not drink grapefruit juice during your treatment with budesonide delayed-release capsules. Drinking grapefruit juice can increase the level of budesonide in your blood.</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of budesonide delayed-release capsules?</span>\n</p>\n<p>\n<span class=\"Bold\">Budesonide delayed-release capsules may cause serious side effects, including:</span>\n</p>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Effects of having too much corticosteroid medicine in your blood (hypercorticism). </span>Long-time use of budesonide delayed-release capsules can cause you to have too much corticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>acne</li>\n<li>bruise easily</li>\n<li>rounding of your face (moon face)</li>\n<li>ankle swelling</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Circle\">\n<li>thicker or more hair on your body and face</li>\n<li>a fatty pad or hump between your shoulders (buffalo hump)</li>\n<li>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Adrenal suppression. </span>When budesonide delayed-release capsules are taken for a long period of time (chronic use), adrenal suppression can happen. This is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal suppression include: tiredness, weakness, nausea and vomiting and low blood pressure. Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide delayed-release capsules.</li>\n<li>\n<span class=\"Bold\">Worsening of allergies. </span>If you take certain other corticosteroid medicines to treat allergies, switching to budesonide delayed-release capsules may cause your allergies to come back. These allergies may include a skin condition called eczema or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while taking budesonide delayed-release capsules.</li>\n<li>\n<p class=\"First\">\n<span class=\"Bold\">Decreased ability of your body to fight infections (immunosuppression) and i</span><span class=\"Bold\">ncreased risk of infection. </span>Corticosteroid medicines, including budesonide delayed-release capsules, lower the ability of your immune system to fight infections and increase the risk of infections caused by virus, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines including budesonide delayed-release capsules can also:</p>\n<ul class=\"Circle\">\n<li>make current infections worse</li>\n<li>increase the risk of infections spreading (disseminated)</li>\n<li>increase the risk of making infections active again or making infections worse that have not been active (latent)</li>\n<li>hide (mask) some signs of infection</li>\n</ul>\n<p>These infections can be mild, but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide delayed-release capsules.</p>\n Tell your healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide delayed-release capsules, including flu-like symptoms such as:</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Circle\">\n<li>fever</li>\n<li>chills</li>\n<li>stomach area (abdominal) pain</li>\n<li>aches</li>\n<li>diarrhea</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Circle\">\n<li>cough</li>\n<li>pain</li>\n<li>feeling tired</li>\n<li>nausea and vomiting</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<ul class=\"Circle\">\n<li>Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide delayed-release capsules your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide delayed-release capsules.</li>\n<li>Chicken pox and measles: People taking corticosteroid medicines, including budesonide delayed-release capsules, who have not had chicken pox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chicken pox or measles.</li>\n<li>Hepatitis B Virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide delayed-release capsules. Your healthcare provider will test you for HBV before you start taking budesonide delayed-release capsules.</li>\n<li>Amebiasis: Inactive (latent) amebiasis before you start taking budesonide delayed-release capsules. Your healthcare provider should check you for amebiasis before you start taking budesonide delayed-release capsules in people who have spent time in the tropics or have unexplained diarrhea.</li>\n</ul>\n<ul class=\"Disc\">\n<li>\n<span class=\"Bold\">Kaposi’s Sarcoma</span>. Kaposi’s sarcoma has happened in people who receive corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions.</li>\n</ul>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of budesonide delayed-release capsules in adults include:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\">\n<ul class=\"Disc\">\n<li>headache</li>\n<li>stomach area (abdominal) pain</li>\n<li>infection in your air passages (respiratory infection)</li>\n<li>gas</li>\n<li>nausea</li>\n</ul>\n</td><td class=\"Rrule\">\n<ul class=\"Disc\">\n<li>vomiting</li>\n<li>back pain</li>\n<li>tiredness</li>\n<li>indigestion</li>\n<li>pain</li>\n<li>dizziness</li>\n</ul>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of budesonide delayed-release capsules in children </span>8 to 17 years of age, who weigh more than 55 pounds (25 kg), are similar to the most common side effects in adults.</p>\n<p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all the possible side effects of budesonide delayed-release capsules. For more information, ask your healthcare provider or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store budesonide delayed-release capsules?</span>\n</p>\n<ul class=\"Disc\">\n<li>Store budesonide delayed-release capsules at room temperature between 20° to 25°C (68° to 77°F).</li>\n<li>Keep budesonide delayed-release capsules in a tightly closed container.</li>\n</ul>\n<p>\n<span class=\"Bold\">Keep budesonide delayed-release capsules and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of budesonide delayed-release capsules.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide or Patient Information leaflet. Do not use budesonide delayed-release capsules for a condition for which it was not prescribed. Do not give budesonide delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about budesonide delayed-release capsules that is written for health professionals.</p>\n<p>For more information go to www.amneal.com or call 1-877-835-5472.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in budesonide delayed-release capsules?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient: </span>budesonide, USP</p>\n<p>\n<span class=\"Bold\">Inactive ingredients: </span>cetyl alcohol, corn starch, ethyl cellulose, hypromellose, macrogol, methacrylic acid copolymer type C, sodium lauryl sulfate, sugar, talc and triethyl citrate.</p>\n<p>The capsule shell contains: D&amp;C yellow #10, FD&amp;C blue #1, FD&amp;C red #40, FD&amp;C yellow #6, gelatin and titanium dioxide.</p>\n<p>The monogramming ink contains: D&amp;C yellow #10, ethanol, FD&amp;C blue #1, FD&amp;C blue #2, FD&amp;C red #40, iron oxide black, methanol, N-butyl alcohol, propylene glycol and shellac.<br/>\n<br/>Manufactured by:<br/>\n<span class=\"Bold\">Amneal Pharmaceuticals Pvt. Ltd.<br/>\n</span>Ahmedabad 382220, INDIA</p>\n<p>Distributed by:<br/>\n<span class=\"Bold\">Amneal Pharmaceuticals LLC<br/>\n</span>Bridgewater, NJ 08807</p>\n<p>This Patient Information has been approved by the U.S. Food and Drug Administration.<br/>\n<br/>\n Rev. 06-2025-01</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Dispense with Patient Information available at: documents.amneal.com/mg/ppi-budesonide-dr-cap.pdf

{ "type": "p", "children": [], "text": "Dispense with Patient Information available at:\ndocuments.amneal.com/mg/ppi-budesonide-dr-cap.pdf" }

NDC 53746-778-10

{ "type": "p", "children": [], "text": "\nNDC 53746-778-10\n" }

Budesonide Delayed-Release Capsules, 3 mg

{ "type": "p", "children": [], "text": "\nBudesonide Delayed-Release Capsules, 3 mg\n" }

Rx only

{ "type": "p", "children": [], "text": "\nRx only\n" }

100 Count

{ "type": "p", "children": [], "text": "\n100 Count\n" }

Amneal Pharmaceuticals LLC

{ "type": "p", "children": [], "text": "\nAmneal Pharmaceuticals LLC\n" }

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

Limitations of Use:

•PULMICORT FLEXHALER is NOT indicated for the relief of acute bronchospasm.

If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.

Patients 18 Years of Age and Older: For patients 18 years of age and older, the recommended starting dosage is 360 mcg twice daily. In some adult patients, a starting dose of 180 mcg twice daily may be adequate. The maximum dosage should not exceed 720 mcg twice daily.

Patients 6 to 17 Years of Age: The recommended starting dosage is 180 mcg twice daily. In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate. The maximum dosage should not exceed 360 mcg twice daily.

For all patients, it is desirable to titrate to the lowest effective dose after adequate asthma stability is achieved.

Improvement in asthma control following inhaled administration of budesonide can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. Individual patients will experience a variable onset and degree of symptom relief.

If a previously effective dosage regimen of PULMICORT FLEXHALER fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g., replacing the lower strength of PULMICORT FLEXHALER with the higher strength or initiating oral corticosteroids) should be considered.

PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg. Each inhaler contains 60 or 120 actuations.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg. Each inhaler contains 60 or 120 actuations." }

The use of PULMICORT FLEXHALER is contraindicated in the following conditions:

{ "type": "p", "children": [], "text": "The use of PULMICORT FLEXHALER is contraindicated in the following conditions:" }

{ "type": "", "children": [], "text": "" }

In clinical studies, the development of localized infections of the mouth and 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 may need to be interrupted. Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.

PULMICORT FLEXHALER is not a bronchodilator and is not indicated for the rapid relief of bronchospasm or other acute episodes of asthma. Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with PULMICORT FLEXHALER. During such episodes, patients may require therapy with oral corticosteroids.

An inhaled short acting beta2-agonist, not PULMICORT FLEXHALER, should be used to relieve acute symptoms such as 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.

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4), Adverse Reactions (6)].

PULMICORT FLEXHALER contains small amounts of 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 (4), Adverse Reactions (6.2)].

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 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 immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.

An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., beta2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥5.0 (gpELISA value) in response to the vaccination was similar in patients treated with 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.

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.

Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT FLEXHALER 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 FLEXHALER 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 FLEXHALER. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with PULMICORT FLEXHALER. Lung function (mean forced expiratory volume in 1 second [FEV1] 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.

Transfer of patients from systemic corticosteroid therapy to PULMICORT FLEXHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, (e.g., 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.

PULMICORT FLEXHALER will often help control asthma symptoms with less suppression of HPA function 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 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.

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.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of PULMICORT FLEXHALER should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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 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.

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 FLEXHALER routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT FLEXHALER, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.1), Use in Specific Populations (8.4)].

Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

As with other inhaled asthma medications, PULMICORT FLEXHALER can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with PULMICORT FLEXHALER, it should be treated immediately with an inhaled, short-acting beta2-bronchodilator. PULMICORT FLEXHALER should be discontinued immediately, and alternative therapy should be instituted.

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 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

PULMICORT FLEXHALER

Patients 6 years and older

The incidence of common adverse reactions in Table 1 is based upon pooled data reported in patients treated with PULMICORT FLEXHALER 180 or 90 mcg in two double-blind, placebo-controlled clinical trials in which 226 patients (106 females and 120 males) with mild to moderate asthma, previously receiving bronchodilators, inhaled corticosteroids, or both, were treated with PULMICORT FLEXHALER, administered as 360 mcg twice daily for 12 weeks. In these trials, the patients on PULMICORT FLEXHALER had a mean age of 28 years (range 6-80 years) and were predominantly Caucasian (59.7%) and Asian (31.4%). Table 1 includes all adverse reactions (regardless of investigator causality assessment) that occurred at a rate of ≥1% in the PULMICORT FLEXHALER group and more commonly than the placebo group.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1 - Adverse Reactions occurring at an incidence of ≥1% and more commonly than placebo in the PULMICORT FLEXHALER group: pooled data from two 12-week, double-blind, placebo-controlled clinical asthma trials in patients 6 years and older</span> </caption> <colgroup> <col width="37%"/> <col width="32%"/> <col width="10%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Adverse Event</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">PULMICORT FLEXHALER</span> </p> <p> <span class="Bold">360 mcg twice daily</span> </p> <p>N=226</p> <p>%</p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p>N=230</p> <p>%</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Nasopharyngitis</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">9.3</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">8.3</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Nasal congestion</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.7</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Pharyngitis</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.7</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.7</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Rhinitis allergic</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.3</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Viral upper respiratory tract infection</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2.2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.3</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.8</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.9</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Viral gastroenteritis</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.8</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Otitis media</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.3</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.9</p> </td> </tr> <tr> <td class="Botrule" valign="top"> <p class="First">Oral candidiasis</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1.3</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0.4</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Average exposure duration (days)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">76.2</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">68.2</p> </td> </tr> </tbody> </table></div>

Long-Term Safety in Patients 6 years of age and older

Non-placebo controlled long-term studies in children (at doses up to 360 mcg daily), and adolescent and adult subjects (at doses up to 720 mcg daily), treated for up to one year with PULMICORT FLEXHALER, revealed a similar pattern and incidence of adverse events.

PULMICORT TURBUHALER; a different PULMICORT DPI

The following adverse reactions occurred in placebo-controlled clinical trials with similar or lower doses with inhaled budesonide via a different PULMICORT dry powder inhaler with an incidence of ≥1% in the budesonide group and were more common than in the placebo group:

≥3%: respiratory infection, sinusitis, headache, pain, back pain, fever.

≥1-3%: neck pain, syncope, abdominal pain, dry mouth, vomiting, weight gain, fracture, myalgia, hypertonia, migraine, ecchymosis, insomnia, infection, taste perversion, voice alteration.

Higher doses of inhaled budesonide (800 mcg twice daily) via a different PULMICORT dry powder inhaler resulted in an increased incidence of voice alteration, flu syndrome, dyspepsia, gastroenteritis, nausea, and back pain, compared with doses of 400 mcg twice daily.

In a 20-week trial in adult asthmatics who previously required oral corticosteroids, the incidence of adverse reactions was evaluated with 400 mcg twice daily (N=53) and 800 mcg twice daily (N=53) of inhaled budesonide via a different PULMICORT dry powder inhaler and compared with placebo (N=53). In considering these data, the increased average duration of exposure for inhaled budesonide patients (78 days for inhaled budesonide vs. 41 days for placebo) should be taken into account. Adverse reactions, regardless of investigator causality assessment, reported in more than five patients in the budesonide group and which occurred more commonly than the placebo group in decreasing order of frequency include: respiratory infection, sinusitis, headache, oral candidiasis, pain, asthenia, dyspepsia, arthralgia, cough increased, nausea and rhinitis.

The following adverse reactions have been reported during post-approval use of PULMICORT FLEXHALER. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: 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 (5.3), Contraindications (4)]

Endocrine disorders: symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.6)]

Eye disorders: cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.10)]

Psychiatric disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety

Respiratory, thoracic, and mediastinal disorders: throat irritation

Skin and subcutaneous tissue disorders: skin bruising

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 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 with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.7)].

Risk Summary

There are no adequate well-controlled studies of PULMICORT FLEXHALER in pregnant women. However, there are published studies on the use of budesonide, the active ingredient in PULMICORT FLEXHALER, in pregnant women. In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the maximum recommended human daily inhalation dose (MRHDID), but these effects were not seen in rats that received inhaled doses approximately 2 times the MRHDID (see Data). Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans.

The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal risk

In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor or Delivery

There are no well-controlled human studies that have investigated the effects of PULMICORT FLEXHALER during labor and delivery.

Data

Human Data

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 (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).

These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Animal Data

In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide 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 doses 0.1 times the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.03 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 5 mcg/kg/day).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.3 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6-15, budesonide produced similar adverse fetal effects at doses approximately 4 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m2 basis at maternal inhalation doses up to 250 mcg/kg/day).

In a peri-and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses 0.1 times the MRHDID and higher (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Risk Summary

There are no available data on the effects of PULMICORT FLEXHALER on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PULMICORT FLEXHALER and any potential adverse effects on the breastfed infant from PULMICORT FLEXHALER or from the underlying maternal condition.

Data

Human data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [seeClinical Pharmacology (12.3)].

In a 12-week pivotal study, 204 patients 6 to 17 years of age were treated with PULMICORT FLEXHALER twice daily [see Clinical Studies (14.1)]. 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.

The safety and effectiveness of PULMICORT FLEXHALER in asthma patients below 6 years of age have not been established.

Controlled clinical studies have shown that orally inhaled corticosteroids, including budesonide, 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 inhaled budesonide via a different PULMICORT dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with a different PULMICORT dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.

The administration of inhaled budesonide via a different PULMICORT dry-powder inhaler 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 inhaled budesonide on growth is not fully known.

The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT FLEXHALER, should be monitored (e.g., 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, each patient should be titrated to the lowest dose that effectively controls his/her asthma [see Dosage and Administration (2)].

Of the total number of patients in controlled clinical studies receiving inhaled budesonide, 153 (n=11 treated with PULMICORT FLEXHALER) were 65 years of age or older and one was age 75 years or older. No overall differences in safety were observed between these patients and younger patients. Clinical studies did not include sufficient numbers of patients aged 65 years and over to determine differences in efficacy between elderly and younger patients. Other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and 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.

Formal pharmacokinetic studies using PULMICORT FLEXHALER have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in the plasma. Therefore, patients with hepatic disease should be closely monitored.

The potential for acute toxic effects following overdose of PULMICORT FLEXHALER is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions (5.6)]. 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.

{ "type": "p", "children": [], "text": "The potential for acute toxic effects following overdose of PULMICORT FLEXHALER is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions (5.6)]. 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. " }

Postmarketing experience showed that 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.

{ "type": "p", "children": [], "text": "Postmarketing experience showed that 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." }

Budesonide, the active component of PULMICORT FLEXHALER, 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 C25H34O6 and its molecular weight is 430.5. Its structural formula is:

{ "type": "p", "children": [], "text": "Budesonide, the active component of PULMICORT FLEXHALER, 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 C25H34O6 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 103.

{ "type": "p", "children": [], "text": "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 103." }

PULMICORT FLEXHALER is an inhalation-driven multi-dose dry powder inhaler containing a formulation of 1 mg per actuation of micronized budesonide and micronized lactose monohydrate which contains trace levels of milk proteins [see Contraindications (4), Adverse Reactions (6.2)]. Each actuation of PULMICORT FLEXHALER 180 mcg delivers 160 mcg budesonide from the mouthpiece and each actuation of PULMICORT FLEXHALER 90 mcg delivers 80 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec). Each PULMICORT FLEXHALER 180 mcg contains 120 actuations and each PULMICORT FLEXHALER 90 mcg contains 60 actuations.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER is an inhalation-driven multi-dose dry powder inhaler containing a formulation of 1 mg per actuation of micronized budesonide and micronized lactose monohydrate which contains trace levels of milk proteins [see Contraindications (4), Adverse Reactions (6.2)]. Each actuation of PULMICORT FLEXHALER 180 mcg delivers 160 mcg budesonide from the mouthpiece and each actuation of PULMICORT FLEXHALER 90 mcg delivers 80 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec). Each PULMICORT FLEXHALER 180 mcg contains 120 actuations and each PULMICORT FLEXHALER 90 mcg contains 60 actuations." }

In vitro testing has shown that the dose delivery for PULMICORT FLEXHALER is dependent on airflow through the device, as evidenced by a decrease in the fine particle dose at a flow rate of 30 L/min to a value that is approximately 40-50% of that produced at 60 L/min. At a flow rate of 40 L/min, the fine particle dose is approximately 70% of that produced at 60 L/min. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use [see Patient Information and Instructions for Use]. In asthmatic children age 6 to 17 (N=516, FEV1 2.29 [0.97– 4.28]) peak inspiratory flow (PIF) through PULMICORT FLEXHALER was 72.5 [19.1 – 103.6] L/min). Inspiratory flows were not measured in the adult pivotal study. Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.

{ "type": "p", "children": [], "text": "\nIn vitro testing has shown that the dose delivery for PULMICORT FLEXHALER is dependent on airflow through the device, as evidenced by a decrease in the fine particle dose at a flow rate of 30 L/min to a value that is approximately 40-50% of that produced at 60 L/min. At a flow rate of 40 L/min, the fine particle dose is approximately 70% of that produced at 60 L/min. Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use [see Patient Information and Instructions for Use]. In asthmatic children age 6 to 17 (N=516, FEV1 2.29 [0.97– 4.28]) peak inspiratory flow (PIF) through PULMICORT FLEXHALER was 72.5 [19.1 – 103.6] L/min). Inspiratory flows were not measured in the adult pivotal study. Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery." }

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 clinical significance of this is unknown.

The activity of PULMICORT FLEXHALER 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 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.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of inhaled 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).

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 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.

Inhaled 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.

Pre-treatment with inhaled budesonide 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV1 following inhaled allergen challenge.

HPA Axis effects: 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.

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 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.

In asthmatic patients, budesonide showed a linear increase in AUC and Cmax with increasing dose after both a single dose and repeated dosing of inhaled 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 FLEXHALER. 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 radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.

Special Populations

No clinically relevant pharmacokinetic differences have been identified due to race, sex, or advanced age.

Geriatric

The pharmacokinetics of PULMICORT FLEXHALER in geriatric patients have not been specifically studied.

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.

Peak steady-state plasma concentrations of budesonide delivered via PULMICORT FLEXHALER in children and adolescents with asthma (n=14) occurred at approximately 15 to 30 minutes post-dose and averaged 0.4 and 1.5 nmol/L at doses of 180 mcg once daily and 360 mcg twice daily, respectively.

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 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 (8.2)].

Renal or Hepatic Insufficiency

There are no data regarding the specific use of PULMICORT FLEXHALER in patients with hepatic or renal impairment. 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

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 (5.7), Drug Interactions (7.1)].

Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral 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 (approximately 0.3 times the MRHDID in adults and children 6 to 17 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 times the MRHDID 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 MRHDID 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 MRHDID 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 MRHDID 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.

There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (approximately 0.7 times the MRHDID in adults and children 6 to 17 years of age on a mcg/m2 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.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg (approximately 0.5 times the MRHDID in adults on a mcg/m2 basis). At a subcutaneous dose of 20 mcg/kg/day (approximately 0.1 times the maximum recommended daily inhalation dose in adults on a mcg/m2 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 MRHDID in adults on a mcg/m2 basis).

The safety and efficacy of PULMICORT FLEXHALER were evaluated in two 12-week, double-blind, randomized, parallel-group, placebo-controlled clinical studies conducted at sites in the United States and Asia involving 1137 patients aged 6 to 80 years with mild to moderate asthma. Study 1 evaluated PULMICORT FLEXHALER 180 mcg, PULMICORT TURBUHALER 200 mcg, and placebo, each administered as 1 inhalation once daily or 2 inhalations twice daily in patients 18 years of age and older with mild to moderate asthma previously treated with inhaled corticosteroids. The delivered dose of PULMICORT FLEXHALER 180 mcg and PULMICORT TURBUHALER 200 mcg are the same; each delivers 160 mcg from the mouthpiece. Study 2 evaluated PULMICORT FLEXHALER 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 FEV1 (adults) or FEV1 % predicted (children).

Patients ≥ 18 years of age and older (Study 1)

This study enrolled 621 patients aged ≥18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids. Mean change from baseline in FEV1 in the PULMICORT FLEXHALER 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 over placebo (p<0.001).

12-Week Trial in Adult Patients with Mild to Moderate Asthma (Study 1) Mean Change from Baseline in FEV1 (L)

Footnote: 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.

Patients 6 to 17 years of age (Study 2)

This study enrolled 516 patients aged 6 to 17 years with mild asthma (mean baseline % predicted FEV1 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 FEV1 during the 12-week treatment period in the PULMICORT FLEXHALER 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 over placebo (p<0.001).

12-Week Trial in Pediatric Patients With Mild Asthma (Study 2) Mean Change from Baseline in Percent Predicted FEV1

Footnote: 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.

PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg. Each dosage strength contains 60 or 120 actuations per device. 180 mcg/dose (NDC 61269-518-12) with a target fill weight of 225 mg (range 200-250), and 90 mcg/dose, 60 dose (NDC 61269-509-06) with a target fill weight of 165 mg (range 140-190).

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg. Each dosage strength contains 60 or 120 actuations per device. 180 mcg/dose (NDC 61269-518-12) with a target fill weight of 225 mg (range 200-250), and 90 mcg/dose, 60 dose (NDC 61269-509-06) with a target fill weight of 165 mg (range 140-190)." }

PULMICORT FLEXHALER 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 PULMICORT FLEXHALER inhaler cannot be refilled and should be discarded when empty.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER 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 PULMICORT FLEXHALER inhaler cannot be refilled and should be discarded when empty." }

The number in the middle of the dose indicator window shows how many doses are left in the inhaler. The inhaler is empty when the number zero (“0”) on the red background reaches the middle of the window. If the unit is used beyond the point at which the zero reaches the middle of the window, the correct amount of medication may not be obtained and the unit should be discarded.

{ "type": "p", "children": [], "text": "The number in the middle of the dose indicator window shows how many doses are left in the inhaler. The inhaler is empty when the number zero (“0”) on the red background reaches the middle of the window. If the unit is used beyond the point at which the zero reaches the middle of the window, the correct amount of medication may not be obtained and the unit should be discarded." }

Store in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP] with the cover tightly in place. Keep out of the reach of children.

{ "type": "p", "children": [], "text": "Store in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP] with the cover tightly in place. Keep out of the reach of children." }

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 FLEXHALER, but at times therapy with PULMICORT FLEXHALER may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)].

PULMICORT FLEXHALER 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 (the physician should provide the patient with such medication and instruct the patient in how it should be used).

Patients should be instructed to notify their physician immediately if they experience any of the following:

   Decreasing effectiveness of inhaled, short-acting beta2-agonists

   Need for more inhalations than usual of inhaled, short-acting beta2-agonists

   Significant decrease in lung function as outlined by the physician

Patients should not stop therapy with PULMICORT FLEXHALER without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.1)].

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4), Warnings and Precautions (5.3), Adverse Reactions (6)].

PULMICORT FLEXHALER contains small amounts of 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 (4)].

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. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.4)].

Patients should be advised that PULMICORT FLEXHALER 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 FLEXHALER [see Warnings and Precautions (5.5, 5.6)].

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 (5.8)].

Patients should be informed that orally inhaled corticosteroids, including budesonide inhalation powder, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.9)].

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 (5.10)].

Patients should be advised to use PULMICORT FLEXHALER at regular intervals, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their physician.

Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery. The patient may not sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER. 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].

PULMICORT FLEXHALER™ (bew DEH so nide) 180 mcg

{ "type": "p", "children": [], "text": "\nPULMICORT FLEXHALER™ (bew DEH so nide) 180 mcg \n" }

(budesonide inhalation powder, 180 mcg)

{ "type": "p", "children": [], "text": "(budesonide inhalation powder, 180 mcg)" }

PULMICORT FLEXHALER™ 90 mcg

{ "type": "p", "children": [], "text": "\nPULMICORT FLEXHALER™ 90 mcg \n" }

(budesonide inhalation powder, 90 mcg)

{ "type": "p", "children": [], "text": "(budesonide inhalation powder, 90 mcg)" }

<div class="scrollingtable"><table width="100%"> <colgroup> <col width="92%"/> </colgroup> <tbody class="Headless"> <tr class="First First Last Last"> <td class="Botrule Lrule Toprule" valign="top"><span class="Bold">Important Note:</span> This medicine is to only be inhaled through the mouth (by oral inhalation only).</td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col width=\"92%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First First Last Last\">\n<td class=\"Botrule Lrule Toprule\" valign=\"top\"><span class=\"Bold\">Important Note:</span> This medicine is to only be inhaled through the mouth (by oral inhalation only).</td>\n</tr>\n</tbody>\n</table></div>" }

Read the Patient Information that comes with PULMICORT FLEXHALER before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment.

{ "type": "p", "children": [], "text": "Read the Patient Information that comes with PULMICORT FLEXHALER before you start using it and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment." }

What is PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nWhat is PULMICORT FLEXHALER?\n" }

PULMICORT FLEXHALER is an inhaled corticosteroid medicine. PULMICORT FLEXHALER is used for long-term (maintenance) treatment of asthma and to prevent asthma symptoms in adults and children 6 years of age and older.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER is an inhaled corticosteroid medicine. PULMICORT FLEXHALER is used for long-term (maintenance) treatment of asthma and to prevent asthma symptoms in adults and children 6 years of age and older." }

Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms.

{ "type": "p", "children": [], "text": "Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms." }

PULMICORT FLEXHALER helps reduce inflammation and helps keep the airways open to reduce asthma symptoms.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER helps reduce inflammation and helps keep the airways open to reduce asthma symptoms." }

PULMICORT FLEXHALER does not treat the symptoms of a sudden asthma attack. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms. If you do not have an inhaled, short-acting bronchodilator, call your healthcare provider to have one prescribed for you.

{ "type": "p", "children": [], "text": "\nPULMICORT FLEXHALER does not treat the symptoms of a sudden asthma attack. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms. If you do not have an inhaled, short-acting bronchodilator, call your healthcare provider to have one prescribed for you. \n" }

It is not known if PULMICORT FLEXHALER is safe and effective in children younger than 6 years of age.

{ "type": "p", "children": [], "text": "It is not known if PULMICORT FLEXHALER is safe and effective in children younger than 6 years of age." }

Who should not use PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nWho should not use PULMICORT FLEXHALER?\n" }

Do not use PULMICORT FLEXHALER:

{ "type": "p", "children": [], "text": "Do not use PULMICORT FLEXHALER:" }

•to treat sudden severe symptoms of asthma.•if you have a severe allergy to milk proteins. PULMICORT FLEXHALER contains a small amount of lactose (milk sugar). People with severe allergies to milk protein may have symptoms of an allergic reaction with PULMICORT FLEXHALER including: cough, wheezing, trouble breathing or feeling like your throat is closing.

{ "type": "p", "children": [], "text": "•to treat sudden severe symptoms of asthma.•if you have a severe allergy to milk proteins. PULMICORT FLEXHALER contains a small amount of lactose (milk sugar). People with severe allergies to milk protein may have symptoms of an allergic reaction with PULMICORT FLEXHALER including: cough, wheezing, trouble breathing or feeling like your throat is closing." }

What should I tell my healthcare provider before using PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before using PULMICORT FLEXHALER?\n" }

Before using PULMICORT FLEXHALER, tell your healthcare provider if you:

{ "type": "p", "children": [], "text": "Before using PULMICORT FLEXHALER, tell your healthcare provider if you:" }

•have any allergies. See the section “Who should not use PULMICORT FLEXHALER”. There is a complete list of ingredients in PULMICORT FLEXHALER at the end of this leaflet.•have or had chicken pox or measles, or have recently been near anyone with chicken pox or measles.•have or had tuberculosis of your respiratory tract.•have certain kinds of serious infections that have not been treated, including:•fungal infections•bacterial infections•viral infections•parasitic infections•herpes simplex infection of the eye (ocular herpes simplex)

{ "type": "p", "children": [], "text": "•have any allergies. See the section “Who should not use PULMICORT FLEXHALER”. There is a complete list of ingredients in PULMICORT FLEXHALER at the end of this leaflet.•have or had chicken pox or measles, or have recently been near anyone with chicken pox or measles.•have or had tuberculosis of your respiratory tract.•have certain kinds of serious infections that have not been treated, including:•fungal infections•bacterial infections•viral infections•parasitic infections•herpes simplex infection of the eye (ocular herpes simplex)" }

PULMICORT FLEXHALER may not be right for people who have or had any of these types of infections.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER may not be right for people who have or had any of these types of infections." }

•have liver problems•have decreased bone mineral density.

{ "type": "p", "children": [], "text": "•have liver problems•have decreased bone mineral density." }

You are at risk for decreased bone mineral density if you:

{ "type": "p", "children": [], "text": "You are at risk for decreased bone mineral density if you:" }

•are inactive for a long period of time•have a family history of osteoporosis•are a woman going through menopause or are past menopause (“the change of life”)•smoke or use tobacco•do not eat well (poor nutrition)•are elderly•take bone thinning medicines (such as anticonvulsant medicines or corticosteroids) for a long time.•have eye problems such as increased pressure in the eye, glaucoma, or cataracts•are planning to have surgery•are pregnant or plan to become pregnant. It is not known if PULMICORT FLEXHALER may harm your unborn baby•are breast-feeding or plan to breast-feed. PULMICORT FLEXHALER can pass into breast milk. You and your healthcare provider should decide if you will use PULMICORT FLEXHALER or breast-feed

{ "type": "p", "children": [], "text": "•are inactive for a long period of time•have a family history of osteoporosis•are a woman going through menopause or are past menopause (“the change of life”)•smoke or use tobacco•do not eat well (poor nutrition)•are elderly•take bone thinning medicines (such as anticonvulsant medicines or corticosteroids) for a long time.•have eye problems such as increased pressure in the eye, glaucoma, or cataracts•are planning to have surgery•are pregnant or plan to become pregnant. It is not known if PULMICORT FLEXHALER may harm your unborn baby•are breast-feeding or plan to breast-feed. PULMICORT FLEXHALER can pass into breast milk. You and your healthcare provider should decide if you will use PULMICORT FLEXHALER or breast-feed" }

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using PULMICORT FLEXHALER with certain other medicines may affect each other causing side effects.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using PULMICORT FLEXHALER with certain other medicines may affect each other causing side effects." }

Especially tell your healthcare provider if you take:

{ "type": "p", "children": [], "text": "Especially tell your healthcare provider if you take:" }

•a corticosteroid medicine•anti-seizure medicine (anticonvulsants)•medicines that suppress your immune system (immunosuppressant)•ketoconazole (Nizoral), other medicines that affect how your liver works.

{ "type": "p", "children": [], "text": "•a corticosteroid medicine•anti-seizure medicine (anticonvulsants)•medicines that suppress your immune system (immunosuppressant)•ketoconazole (Nizoral), other medicines that affect how your liver works." }

Ask your healthcare provider or pharmacist if you are not sure if your medicine is one listed above.

{ "type": "p", "children": [], "text": "Ask your healthcare provider or pharmacist if you are not sure if your medicine is one listed above." }

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine." }

How should I use PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nHow should I use PULMICORT FLEXHALER?\n" }

Use PULMICORT FLEXHALER exactly as prescribed by your healthcare provider. You must use PULMICORT FLEXHALER regularly for it to work.

{ "type": "p", "children": [], "text": "Use PULMICORT FLEXHALER exactly as prescribed by your healthcare provider. You must use PULMICORT FLEXHALER regularly for it to work." }

•PULMICORT FLEXHALER comes in two strengths. Your healthcare provider has prescribed the strength that is best for you.•Be sure you know the difference between PULMICORT FLEXHALER and any other inhaled medicines that are prescribed for you, including what you use them for (prescribed use) and what they look like.•Do not stop using PULMICORT FLEXHALER, even if your symptoms get better. Your healthcare provider will change your medicines as needed.•Do not change or stop any medicines used to control or treat your breathing problems, unless your healthcare provider tells you to.•Rinse your mouth with water and spit the water out after each dose of PULMICORT FLEXHALER. Do not swallow the water. This will lessen the chance of getting a fungal infection (thrush) in the mouth.•If you miss a dose, just take your next regularly scheduled dose when it is due. Do not use PULMICORT FLEXHALER more often or use more puffs than you have been prescribed.•Make sure you always have a short-acting beta2-agonist medicine with you. Use your short acting beta2-agonist medicine if you have breathing problems between doses of PULMICORT FLEXHALER or if a sudden asthma   attack happens. Call your healthcare provider right away if:∘your short-acting rescue medicine does not work as well for relieving asthma symptoms.∘you need to use your short-acting rescue medicines more often than usual.∘your breathing problems worsen with PULMICORT FLEXHALER.

{ "type": "p", "children": [], "text": "•PULMICORT FLEXHALER comes in two strengths. Your healthcare provider has prescribed the strength that is best for you.•Be sure you know the difference between PULMICORT FLEXHALER and any other inhaled medicines that are prescribed for you, including what you use them for (prescribed use) and what they look like.•Do not stop using PULMICORT FLEXHALER, even if your symptoms get better. Your healthcare provider will change your medicines as needed.•Do not change or stop any medicines used to control or treat your breathing problems, unless your healthcare provider tells you to.•Rinse your mouth with water and spit the water out after each dose of PULMICORT FLEXHALER. Do not swallow the water. This will lessen the chance of getting a fungal infection (thrush) in the mouth.•If you miss a dose, just take your next regularly scheduled dose when it is due. Do not use PULMICORT FLEXHALER more often or use more puffs than you have been prescribed.•Make sure you always have a short-acting beta2-agonist medicine with you. Use your short acting beta2-agonist medicine if you have breathing problems between doses of PULMICORT FLEXHALER or if a sudden asthma   attack happens. Call your healthcare provider right away if:∘your short-acting rescue medicine does not work as well for relieving asthma symptoms.∘you need to use your short-acting rescue medicines more often than usual.∘your breathing problems worsen with PULMICORT FLEXHALER." }

If you use another inhaled medicine by mouth to treat your asthma, talk with your healthcare provider for instructions about when to use the other medicine and when to use your PULMICORT FLEXHALER.

{ "type": "p", "children": [], "text": "If you use another inhaled medicine by mouth to treat your asthma, talk with your healthcare provider for instructions about when to use the other medicine and when to use your PULMICORT FLEXHALER." }

•If you have used corticosteroid medicines for a long time and the dose is now being lowered or stopped, you should carry a medical alert card. The medical alert card should state that you may need increased corticosteroids during times of stress or during an asthma attack that does not get better with bronchodilator medicines.•Your healthcare provider may check your breathing, do blood tests and eye exams during treatment with PULMICORT FLEXHALER.•Be sure to read, understand and follow the detailed Patient Instructions for Use at the end of this leaflet. These Instructions for Use tell you how to prime and use your PULMICORT FLEXHALER the right way.

{ "type": "p", "children": [], "text": "•If you have used corticosteroid medicines for a long time and the dose is now being lowered or stopped, you should carry a medical alert card. The medical alert card should state that you may need increased corticosteroids during times of stress or during an asthma attack that does not get better with bronchodilator medicines.•Your healthcare provider may check your breathing, do blood tests and eye exams during treatment with PULMICORT FLEXHALER.•Be sure to read, understand and follow the detailed Patient Instructions for Use at the end of this leaflet. These Instructions for Use tell you how to prime and use your PULMICORT FLEXHALER the right way." }

What are the possible side effects of PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of PULMICORT FLEXHALER?\n" }

PULMICORT FLEXHALER can cause serious side effects, including:

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER can cause serious side effects, including:" }

•thrush (candida), a fungal infection in your mouth and throat. Tell your healthcare provider if you have any redness or white colored patches in your mouth or throat.•worsening of asthma or sudden asthma attacks.•allergic reactions. Tell your healthcare provider or get medical help right away if you have:∘skin rash, redness or swelling∘severe itching∘swelling of the face, mouth, and tongue∘trouble breathing or swallowing∘chest pain∘anxiety (feeling of doom)•Immune system effects and a higher chance of infections. You are more likely to get infections if you take medicines that weaken your immune system. Avoid contact with people who have contagious diseases such as chicken pox or measles while using PULMICORT FLEXHALER. Symptoms of infection may include: fever, pain, aches, chills, feeling tired, nausea and vomiting. Tell your healthcare provider about any signs of infection while you are using PULMICORT FLEXHALER.•Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency include: tiredness, weakness, nausea and vomiting and low blood pressure.•Decrease in bone mineral density. Your healthcare provider should check you for this during treatment with PULMICORT FLEXHALER.•Slowed or delayed growth problems in children. A child’s growth should be checked regularly while using PULMICORT FLEXHALER.•Eye problems, including glaucoma and cataracts. You should have regular eye exams while using PULMICORT FLEXHALER.•Increased wheezing right after taking PULMICORT FLEXHALER. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden wheezing.

{ "type": "p", "children": [], "text": "•thrush (candida), a fungal infection in your mouth and throat. Tell your healthcare provider if you have any redness or white colored patches in your mouth or throat.•worsening of asthma or sudden asthma attacks.•allergic reactions. Tell your healthcare provider or get medical help right away if you have:∘skin rash, redness or swelling∘severe itching∘swelling of the face, mouth, and tongue∘trouble breathing or swallowing∘chest pain∘anxiety (feeling of doom)•Immune system effects and a higher chance of infections. You are more likely to get infections if you take medicines that weaken your immune system. Avoid contact with people who have contagious diseases such as chicken pox or measles while using PULMICORT FLEXHALER. Symptoms of infection may include: fever, pain, aches, chills, feeling tired, nausea and vomiting. Tell your healthcare provider about any signs of infection while you are using PULMICORT FLEXHALER.•Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency include: tiredness, weakness, nausea and vomiting and low blood pressure.•Decrease in bone mineral density. Your healthcare provider should check you for this during treatment with PULMICORT FLEXHALER.•Slowed or delayed growth problems in children. A child’s growth should be checked regularly while using PULMICORT FLEXHALER.•Eye problems, including glaucoma and cataracts. You should have regular eye exams while using PULMICORT FLEXHALER.•Increased wheezing right after taking PULMICORT FLEXHALER. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden wheezing." }

Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.

{ "type": "p", "children": [], "text": "\nCall your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.\n" }

Common side effects reported by patients using PULMICORT FLEXHALER include:

{ "type": "p", "children": [], "text": "Common side effects reported by patients using PULMICORT FLEXHALER include:" }

•sore nose and throat•stuffy nose•runny nose•nausea•hay fever•viral infections of the upper respiratory tract•viral irritation and inflammation of the stomach and intestine (gastroenteritis). Symptoms may include stomach area pain, diarrhea, nausea and vomiting, loss of appetite, headaches, and weakness.•ear infections

{ "type": "p", "children": [], "text": "•sore nose and throat•stuffy nose•runny nose•nausea•hay fever•viral infections of the upper respiratory tract•viral irritation and inflammation of the stomach and intestine (gastroenteritis). Symptoms may include stomach area pain, diarrhea, nausea and vomiting, loss of appetite, headaches, and weakness.•ear infections" }

Tell your healthcare provider about any side effect that bothers you or that does not go away.

{ "type": "p", "children": [], "text": "Tell your healthcare provider about any side effect that bothers you or that does not go away." }

These are not all of the side effects of PULMICORT FLEXHALER. Ask your healthcare provider or pharmacist for more information.

{ "type": "p", "children": [], "text": "These are not all of the side effects of PULMICORT FLEXHALER. Ask your healthcare provider or pharmacist for more information." }

Call your healthcare provider for medical advice about side effects. You may report side effects to the Safety Call Center at 1-888-994-8116 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "Call your healthcare provider for medical advice about side effects. You may report side effects to the Safety Call Center at 1-888-994-8116 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." }

How should I store PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nHow should I store PULMICORT FLEXHALER?\n" }

Store PULMICORT FLEXHALER at 68° to 77°F (20° to 25°C).

{ "type": "p", "children": [], "text": "Store PULMICORT FLEXHALER at 68° to 77°F (20° to 25°C)." }

•Keep PULMICORT FLEXHALER dry.•Keep your PULMICORT FLEXHALER with the cover tightly in place when not in use.

{ "type": "p", "children": [], "text": "•Keep PULMICORT FLEXHALER dry.•Keep your PULMICORT FLEXHALER with the cover tightly in place when not in use." }

Keep your PULMICORT FLEXHALER and all medicines out of the reach of children.

{ "type": "p", "children": [], "text": "\nKeep your PULMICORT FLEXHALER and all medicines out of the reach of children. \n" }

General Information about PULMICORT FLEXHALER

{ "type": "p", "children": [], "text": "\nGeneral Information about PULMICORT FLEXHALER\n" }

Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information Leaflets. Do not use PULMICORT FLEXHALER for a condition for which it was not prescribed. Do not give PULMICORT FLEXHALER to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information Leaflets. Do not use PULMICORT FLEXHALER for a condition for which it was not prescribed. Do not give PULMICORT FLEXHALER to other people, even if they have the same symptoms that you have. It may harm them." }

This Patient Information leaflet summarizes the most important information about PULMICORT FLEXHALER. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PULMICORT FLEXHALER that is written for health professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about PULMICORT FLEXHALER. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about PULMICORT FLEXHALER that is written for health professionals." }

For more information, go to pulmicortflexhaler.com or call 1- 888-994-8116.

{ "type": "p", "children": [], "text": "For more information, go to pulmicortflexhaler.com or call 1- 888-994-8116." }

What are the ingredients in PULMICORT FLEXHALER?

{ "type": "p", "children": [], "text": "\nWhat are the ingredients in PULMICORT FLEXHALER?\n" }

Active ingredient: budesonide

{ "type": "p", "children": [], "text": "Active ingredient: budesonide" }

Inactive ingredient: lactose

{ "type": "p", "children": [], "text": "Inactive ingredient: lactose" }

Patient Instructions for Use

{ "type": "p", "children": [], "text": "\nPatient Instructions for Use \n" }

How to use your PULMICORT FLEXHALER

{ "type": "p", "children": [], "text": "\nHow to use your PULMICORT FLEXHALER\n" }

Parts of your PULMICORT FLEXHALER

{ "type": "p", "children": [], "text": "\nParts of your PULMICORT FLEXHALER\n" }

Figure 1

{ "type": "p", "children": [], "text": "Figure 1" }

Priming PULMICORT FLEXHALER:

{ "type": "p", "children": [], "text": "\nPriming PULMICORT FLEXHALER:\n" }

Before you use a new PULMICORT FLEXHALER for the first time, you must prime it.

{ "type": "p", "children": [], "text": "\nBefore you use a new PULMICORT FLEXHALER for the first time, you must prime it.\n" }

To prime your PULMICORT FLEXHALER, follow the steps below:

{ "type": "p", "children": [], "text": "To prime your PULMICORT FLEXHALER, follow the steps below:" }

•Hold the inhaler by the brown grip so that the white cover points upward (upright position). With the other hand, turn the white cover and lift it off (see Figure 2).•Continue to hold your PULMICORT FLEXHALER upright as shown in Figure 1. Use your other hand to hold the inhaler in the middle. Do not hold the inhaler at the top of the mouthpiece.•Twist the brown grip as far as it will go in one direction and then fully back again in the other direction until it stops (it does not matter which way you turn it first). You will hear a “click” during one of the twisting movements (see Figures 3 and 4).•Repeat Step 3. Your PULMICORT FLEXHALER is now primed. You are ready to load your first dose.

{ "type": "p", "children": [], "text": "•Hold the inhaler by the brown grip so that the white cover points upward (upright position). With the other hand, turn the white cover and lift it off (see Figure 2).•Continue to hold your PULMICORT FLEXHALER upright as shown in Figure 1. Use your other hand to hold the inhaler in the middle. Do not hold the inhaler at the top of the mouthpiece.•Twist the brown grip as far as it will go in one direction and then fully back again in the other direction until it stops (it does not matter which way you turn it first). You will hear a “click” during one of the twisting movements (see Figures 3 and 4).•Repeat Step 3. Your PULMICORT FLEXHALER is now primed. You are ready to load your first dose." }

You do not have to prime your PULMICORT FLEXHALER again after this even if you do not use it for a long period of time.

{ "type": "p", "children": [], "text": "\nYou do not have to prime your PULMICORT FLEXHALER again after this even if you do not use it for a long period of time.\n" }

1 Loading a dose

{ "type": "p", "children": [], "text": "\n1 Loading a dose\n" }

•Hold your PULMICORT FLEXHALER upright as described above. With your other hand, twist the white cover and lift it off (see Figure 2).

{ "type": "p", "children": [], "text": "•Hold your PULMICORT FLEXHALER upright as described above. With your other hand, twist the white cover and lift it off (see Figure 2)." }

Figure 2

{ "type": "p", "children": [], "text": "Figure 2" }

•Continue to hold your PULMICORT FLEXHALER upright to be sure that the right dose of medicine is loaded.•Use your other hand to hold the inhaler in the middle. Do not hold the mouthpiece when you load the inhaler.•Twist the brown grip fully in one direction as far as it will go. Twist it fully back again in the other direction as far as it will go (it does not matter which way you turn it first) [see Figure 3].

{ "type": "p", "children": [], "text": "•Continue to hold your PULMICORT FLEXHALER upright to be sure that the right dose of medicine is loaded.•Use your other hand to hold the inhaler in the middle. Do not hold the mouthpiece when you load the inhaler.•Twist the brown grip fully in one direction as far as it will go. Twist it fully back again in the other direction as far as it will go (it does not matter which way you turn it first) [see Figure 3]." }

Figure 3

{ "type": "p", "children": [], "text": "Figure 3" }

•You will hear a “click” during one of the twisting movements (see Figure 4).

{ "type": "p", "children": [], "text": "•You will hear a “click” during one of the twisting movements (see Figure 4)." }

Figure 4

{ "type": "p", "children": [], "text": "Figure 4" }

•PULMICORT FLEXHALER will only give one dose at a time, no matter how often you click the brown grip, but the dose indicator will continue to move (advance). This means that if you continue to move the brown grip, it is possible for the indicator to show fewer doses or zero doses even if more doses are left in the inhaler.•Do not shake the inhaler after loading it.

{ "type": "p", "children": [], "text": "•PULMICORT FLEXHALER will only give one dose at a time, no matter how often you click the brown grip, but the dose indicator will continue to move (advance). This means that if you continue to move the brown grip, it is possible for the indicator to show fewer doses or zero doses even if more doses are left in the inhaler.•Do not shake the inhaler after loading it.\n" }

Figure 5

{ "type": "p", "children": [], "text": "Figure 5" }

2 Inhaling a dose

{ "type": "p", "children": [], "text": "\n2 Inhaling a dose\n" }

•Turn your head away from the inhaler and breathe out (exhale). If you accidentally blow into your inhaler after loading a dose, follow the instructions for loading a new dose.•Place the mouthpiece in your mouth and close your lips around the mouthpiece. Breathe in (inhale) deeply and forcefully through the inhaler (see Figure 5).•You may not sense the presence of any medication entering your lungs when inhaling from PULMICORT FLEXHALER. This lack of sensation does not mean that you did not get the medication. You should not repeat your inhalations even if you did not feel the medication when inhaling.•Do not chew or bite on the mouthpiece.•Remove the inhaler from your mouth and exhale. Do not blow or exhale into the mouthpiece.•If more than one dose is prescribed repeat the steps above.•When you are finished taking your dose place the white cover back on the inhaler and twist shut.•Rinse your mouth with water after each dose to decrease your risk of getting thrush. Do not swallow the water.

{ "type": "p", "children": [], "text": "•Turn your head away from the inhaler and breathe out (exhale). If you accidentally blow into your inhaler after loading a dose, follow the instructions for loading a new dose.•Place the mouthpiece in your mouth and close your lips around the mouthpiece. Breathe in (inhale) deeply and forcefully through the inhaler (see Figure 5).•You may not sense the presence of any medication entering your lungs when inhaling from PULMICORT FLEXHALER. This lack of sensation does not mean that you did not get the medication. You should not repeat your inhalations even if you did not feel the medication when inhaling.•Do not chew or bite on the mouthpiece.•Remove the inhaler from your mouth and exhale. Do not blow or exhale into the mouthpiece.•If more than one dose is prescribed repeat the steps above.•When you are finished taking your dose place the white cover back on the inhaler and twist shut.•Rinse your mouth with water after each dose to decrease your risk of getting thrush. Do not swallow the water.\n" }

Reading the Dose Indicator Window

{ "type": "p", "children": [], "text": "\nReading the Dose Indicator Window\n" }

•The label on the box or cover will tell you how many doses are in your PULMICORT FLEXHALER.•Your PULMICORT FLEXHALER has a dose indicator window just below the mouthpiece. The dose indicator tells you about how many doses are left in the inhaler. Look at the middle of the window to find out about how many doses are left in your inhaler (see Figure 6).

{ "type": "p", "children": [], "text": "•The label on the box or cover will tell you how many doses are in your PULMICORT FLEXHALER.•Your PULMICORT FLEXHALER has a dose indicator window just below the mouthpiece. The dose indicator tells you about how many doses are left in the inhaler. Look at the middle of the window to find out about how many doses are left in your inhaler (see Figure 6)." }

Figure 6

{ "type": "p", "children": [], "text": "Figure 6" }

•The dose indicator is connected to the turning grip and moves (counts down) every time a dose is loaded. It is not likely that you will see the dose indicator move with each dose.You can usually see the indicator move each time you use about 5 doses.•The dose indicator starts with either the number 60 or 120 when full, depending upon the strength of the inhaler. The indicator is marked in intervals of 10 doses. Markings are either with numbers or dashes (alternating), counting down to “0”.

{ "type": "p", "children": [], "text": "•The dose indicator is connected to the turning grip and moves (counts down) every time a dose is loaded. It is not likely that you will see the dose indicator move with each dose.You can usually see the indicator move each time you use about 5 doses.•The dose indicator starts with either the number 60 or 120 when full, depending upon the strength of the inhaler. The indicator is marked in intervals of 10 doses. Markings are either with numbers or dashes (alternating), counting down to “0”." }

<div class="scrollingtable"><table width="100%"> <colgroup> <col width="7%"/> <col width="6%"/> <col width="5%"/> <col width="5%"/> <col width="8%"/> <col width="5%"/> <col width="31%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top">60 Dose Inhaler</td><td align="center" class="Botrule Lrule Rrule Toprule" colspan="3" valign="top">120 Dose Inhaler</td><td class="Botrule Lrule Rrule Toprule" valign="top"></td> </tr> <tr> <td class="Lrule Toprule" valign="top"></td><td class="Toprule" valign="top">20</td><td class="Rrule Toprule" valign="top"></td><td class="Lrule Toprule" valign="top"></td><td valign="top">80</td><td class="Rrule" valign="top"></td><td class="Botrule Lrule Rrule Toprule" rowspan="6" valign="top">Dose indicator starts at 60 or 120 depending on strength (90 mcg or 180 mcg) of the inhaler and counts down to 0.</td> </tr> <tr> <td class="Lrule" valign="top"></td><td class="Botrule" valign="top">--</td><td class="Rrule" valign="top"></td><td class="Lrule" valign="top"></td><td class="Botrule" valign="top">--</td><td class="Rrule" valign="top"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule Toprule" valign="top">40</td><td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule Toprule" valign="top">100</td><td class="Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule" valign="top">--</td><td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule" valign="top">--</td><td class="Lrule Rrule" valign="top"></td> </tr> <tr> <td class="Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top">60</td><td class="Lrule Rrule" valign="top"></td><td class="Lrule Rrule" valign="top"></td><td class="Botrule Lrule Rrule" valign="top">120</td><td class="Lrule Rrule" valign="top"></td> </tr> <tr class="Last"> <td class="Botrule Lrule" valign="top">.</td><td class="Botrule Toprule" valign="top"></td><td class="Botrule Rrule" valign="top"></td><td class="Botrule Lrule" valign="top"></td><td class="Botrule Toprule" valign="top"></td><td class="Botrule Rrule" valign="top"></td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<colgroup>\n<col width=\"7%\"/>\n<col width=\"6%\"/>\n<col width=\"5%\"/>\n<col width=\"5%\"/>\n<col width=\"8%\"/>\n<col width=\"5%\"/>\n<col width=\"31%\"/>\n</colgroup>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">60 Dose Inhaler</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"3\" valign=\"top\">120 Dose Inhaler</td><td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Toprule\" valign=\"top\"></td><td class=\"Toprule\" valign=\"top\">20</td><td class=\"Rrule Toprule\" valign=\"top\"></td><td class=\"Lrule Toprule\" valign=\"top\"></td><td valign=\"top\">80</td><td class=\"Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule Toprule\" rowspan=\"6\" valign=\"top\">Dose indicator starts at 60 or 120 depending on strength (90 mcg or 180 mcg) of the inhaler and counts down to 0.</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\"></td><td class=\"Botrule\" valign=\"top\">--</td><td class=\"Rrule\" valign=\"top\"></td><td class=\"Lrule\" valign=\"top\"></td><td class=\"Botrule\" valign=\"top\">--</td><td class=\"Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule Toprule\" valign=\"top\">40</td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule Toprule\" valign=\"top\">100</td><td class=\"Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule\" valign=\"top\">--</td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule\" valign=\"top\">--</td><td class=\"Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\">60</td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Lrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule Rrule\" valign=\"top\">120</td><td class=\"Lrule Rrule\" valign=\"top\"></td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule\" valign=\"top\">.</td><td class=\"Botrule Toprule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td><td class=\"Botrule Lrule\" valign=\"top\"></td><td class=\"Botrule Toprule\" valign=\"top\"></td><td class=\"Botrule Rrule\" valign=\"top\"></td>\n</tr>\n</tbody>\n</table></div>" }

Figure 7

{ "type": "p", "children": [], "text": "Figure 7" }

•Do not put your PULMICORT FLEXHALER in water (do not immerse it) to find out if it is empty. Check the dose indicator window to see how many doses are left.•Refill your PULMICORT FLEXHALER prescription before your medicine runs out. You will get a new inhaler each time you refill your prescription.

{ "type": "p", "children": [], "text": "•Do not put your PULMICORT FLEXHALER in water (do not immerse it) to find out if it is empty. Check the dose indicator window to see how many doses are left.•Refill your PULMICORT FLEXHALER prescription before your medicine runs out. You will get a new inhaler each time you refill your prescription." }

Cleaning your PULMICORT FLEXHALER

{ "type": "p", "children": [], "text": "\nCleaning your PULMICORT FLEXHALER\n" }

•Keep your PULMICORT FLEXHALER clean and dry at all times. Do not immerse it in water.•Wipe the outside of the mouthpiece one time each week with a dry tissue.•Do not use water or liquids when cleaning the mouthpiece.•Do not try to remove the mouthpiece or twist it.

{ "type": "p", "children": [], "text": "•Keep your PULMICORT FLEXHALER clean and dry at all times. Do not immerse it in water.•Wipe the outside of the mouthpiece one time each week with a dry tissue.•Do not use water or liquids when cleaning the mouthpiece.•Do not try to remove the mouthpiece or twist it." }

Do not use your PULMICORT FLEXHALER if it has been damaged or if the mouthpiece has become detached. Talk to your healthcare provider or pharmacist if you have any problems with your PULMICORT FLEXHALER.

{ "type": "p", "children": [], "text": "\nDo not use your PULMICORT FLEXHALER if it has been damaged or if the mouthpiece has become detached. Talk to your healthcare provider or pharmacist if you have any problems with your PULMICORT FLEXHALER.\n" }

PULMICORT FLEXHALER is a trademark of the AstraZeneca group of companies.

{ "type": "p", "children": [], "text": "PULMICORT FLEXHALER is a trademark of the AstraZeneca group of companies." }

©AstraZeneca 2007, 2008, 2010, 2016, 2019

{ "type": "p", "children": [], "text": "©AstraZeneca 2007, 2008, 2010, 2016, 2019" }

Distributed by: H2-Pharma, LLC Montgomery, AL 36117, USA

{ "type": "p", "children": [], "text": "Distributed by: H2-Pharma, LLC\nMontgomery, AL 36117, USA" }

Licensed by: CHEPLAPHARM Arzneimittel GmbH Ziegelhof 24, 17489 Greifswald, Germany

{ "type": "p", "children": [], "text": "Licensed by: CHEPLAPHARM Arzneimittel GmbH\nZiegelhof 24, 17489 Greifswald, Germany" }

Product of Sweden

{ "type": "p", "children": [], "text": "\nProduct of Sweden\n" }

NDC 61269-509-06

{ "type": "p", "children": [], "text": "NDC 61269-509-06" }

Pulmicort

{ "type": "p", "children": [], "text": "Pulmicort" }

Flexhaler™ 90 mcg

{ "type": "p", "children": [], "text": "Flexhaler™ 90 mcg" }

(budesonide inhalation

{ "type": "p", "children": [], "text": "(budesonide inhalation" }

powder, 90 mcg)

{ "type": "p", "children": [], "text": "powder, 90 mcg)" }

90 mcg

{ "type": "p", "children": [], "text": "90 mcg" }

For Oral Inhalation.

{ "type": "p", "children": [], "text": "For Oral Inhalation." }

60 Metered Doses

{ "type": "p", "children": [], "text": "60 Metered Doses" }

Dispense with enclosed Patient

{ "type": "p", "children": [], "text": "Dispense with enclosed Patient" }

Information and Instructions for Use.

{ "type": "p", "children": [], "text": "Information and Instructions for Use." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

CHEPLAPHARM

{ "type": "p", "children": [], "text": "CHEPLAPHARM" }

NDC 61269-518-12

{ "type": "p", "children": [], "text": "NDC 61269-518-12" }

Pulmicort

{ "type": "p", "children": [], "text": "Pulmicort" }

Flexhaler™ 180 mcg

{ "type": "p", "children": [], "text": "Flexhaler™ 180 mcg" }

(budesonide inhalation

{ "type": "p", "children": [], "text": "(budesonide inhalation" }

powder, 180 mcg)

{ "type": "p", "children": [], "text": "powder, 180 mcg)" }

180 mcg

{ "type": "p", "children": [], "text": "180 mcg" }

For Oral Inhalation.

{ "type": "p", "children": [], "text": "For Oral Inhalation." }

120 Metered Doses

{ "type": "p", "children": [], "text": "120 Metered Doses" }

Dispense with enclosed Patient

{ "type": "p", "children": [], "text": "Dispense with enclosed Patient" }

Information and Instructions for Use.

{ "type": "p", "children": [], "text": "Information and Instructions for Use." }

Rx only

{ "type": "p", "children": [], "text": "Rx only" }

CHEPLAPHARM

{ "type": "p", "children": [], "text": "CHEPLAPHARM" }

Budesonide inhalation suspension is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age.

Limitations of Use:

Dosing recommendations based on previous therapy are as follows:

In symptomatic children not responding to non-steroidal therapy, a starting dose of 0.25 mg once daily may be considered. If once-daily treatment does not provide adequate control, the total daily dose should be increased and/or administered as a divided dose. In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved.

Budesonide inhalation suspension should be administered via jet nebulizer connected to an air compressor with an adequate air flow, equipped with a mouthpiece or suitable face mask. Ultrasonic nebulizers are not suitable for the adequate administration of budesonide inhalation suspension and, therefore, are NOT recommended.

The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Patient Counseling Information (17.1)].

A Pari-LC-Jet Plus Nebulizer (with face mask or mouthpiece) connected to a Pari Master compressor was used to deliver budesonide inhalation suspension to each patient in 3 U.S. controlled clinical studies. The safety and efficacy of budesonide inhalation suspension delivered by other nebulizers and compressors have not been established.

Budesonide inhalation suspension is available in single strength: 0.5 mg/ 2mL. Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes each containing one single-dose ampule. There are 30 ampules in a carton. Each single-dose ampule contains 2 mL of sterile liquid suspension.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is available in single strength: 0.5 mg/ 2mL. Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes \n each containing one single-dose ampule.\n\nThere are 30 ampules in a carton. Each single-dose ampule contains 2 mL of sterile liquid suspension.\n " }

The use of budesonide inhalation suspension is contraindicated in the following conditions:

{ "type": "p", "children": [], "text": "The use of budesonide inhalation suspension is contraindicated in the following conditions:" }

{ "type": "ul", "children": [ "Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.", "Hypersensitivity to budesonide or any of the ingredients of budesonide inhalation suspension \n [see \n Warnings and Precautions (5.3), \n Description (11) and \n Adverse Reactions (6.2)]. \n \n" ], "text": "" }

In clinical trials with 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 budesonide inhalation suspension treatment groups. If these infections develop, they may require treatment with appropriate local or systemic antifungal therapy and/or discontinuance of treatment with budesonide inhalation suspension. Patients should rinse the mouth after inhalation of budesonide inhalation suspension.

Budesonide inhalation suspension is not a bronchodilator and is not indicated for the rapid relief of acute bronchospasm or other acute episodes of asthma.

Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with budesonide inhalation suspension. During such episodes, patients may require therapy with oral corticosteroids.

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension. Discontinue budesonide inhalation suspension if such reactions occur [see Contraindications (4)].

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases, or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered.

The clinical course of chicken pox or measles infection in patients on inhaled corticosteroids has not been studied. However, a clinical study has examined the immune responsiveness of asthma patients 12 months to 8 years of age who were treated with 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 budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., beta 2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of ≥5.0 (gpELISA value) in response to the vaccination was similar in patients treated with 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.

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.

Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA)-axis function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.

During this period of HPA-axis suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although budesonide inhalation suspension may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticosteroid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instructions. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to budesonide inhalation suspension. Initially, budesonide inhalation suspension should be used concurrently with the patient's usual maintenance dose of systemic corticosteroid. After approximately one week, gradual withdrawal of the systemic corticosteroid may be initiated by reducing the daily or alternate daily dose. Further incremental reductions may be made after an interval of one or two weeks, depending on the response of the patient. Generally, these decrements should not exceed 25% of the prednisone dose or its equivalent. A slow rate of withdrawal is strongly recommended.

Lung function (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 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 (2)].

During withdrawal from oral corticosteroids, patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

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 budesonide inhalation suspension. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with budesonide inhalation suspension should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients post-operatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism, and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of budesonide inhalation suspension should be reduced slowly, consistent with accepted procedures for tapering of systemic corticosteroids and for management of asthma.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term outcomes is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), should be monitored and treated with established standards of care.

Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving budesonide inhalation suspension routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including budesonide inhalation suspension, each patient should be titrated to his/her lowest effective dose [see Use in Specific Populations (8.4)].

Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If acute bronchospasm occurs following dosing with budesonide inhalation suspension, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with budesonide inhalation suspension should be discontinued and alternate therapy instituted.

In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroids therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Healthcare providers should be alert to eosinophilia, vasculitis rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.

Caution should be exercised when considering the coadministration of budesonide inhalation suspension with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence of common adverse reactions is based on three double-blind, placebo-controlled, randomized U.S. clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients ≥12 months and <2 years of age; 225 patients ≥2 and <4 years of age; and 622 patients ≥4 and ≤8 years of age) were treated with budesonide inhalation suspension (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse events reported for budesonide inhalation suspension was comparable to that reported for placebo. The following table shows the incidence of adverse events in U.S. controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators and/or inhaled corticosteroids. This population included a total of 605 male and 340 female patients and 78.4% were Caucasian, 13.8% African American, 5.5% Hispanic and 2.3% Other.

<div class="scrollingtable"><table width="100%"> <caption> <span>Table 1: Adverse Reactions occurring at an incidence of ≥3% in at least one active treatment group where the incidence was higher with Budesonide Inhalation Suspension than placebo</span> </caption> <colgroup> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> </colgroup> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Adverse Events</span> </p> </td><td align="center" class="Botrule Rrule Toprule" rowspan="2" valign="middle"> <p class="First"> <span class="Bold">Vehicle Placebo</span> </p> <p> <span class="Bold">(n=227)</span> </p> <p> <span class="Bold">%</span> </p> </td><td align="center" class="Botrule Rrule Toprule" colspan="3" valign="middle"> <p class="First"> <span class="Bold">Budesonide Inhalation Suspension</span> </p> <p> <span class="Bold">Total Daily Dose</span> </p> </td> </tr> <tr> <td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">0.25 mg</span> </p> <p> <span class="Bold">(n=178)</span> </p> <p> <span class="Bold">%</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">0.5 mg</span> </p> <p> <span class="Bold">(n=223)</span> </p> <p> <span class="Bold">%</span> </p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First"> <span class="Bold">1 mg</span> </p> <p> <span class="Bold">(n=317)</span> </p> <p> <span class="Bold">%</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Respiratory System Disorder</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Respiratory Infection</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">36</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">34</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">35</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">38</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rhinitis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">7</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">12</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Coughing</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">9</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">8</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Resistance Mechanism Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Otitis Media</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">12</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">11</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">9</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Viral Infection</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Moniliasis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Gastrointestinal System Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Gastroenteritis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Vomiting</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Diarrhea</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Abdominal Pain</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Hearing and Vestibular Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Ear Infection</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">5</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Platelet, Bleeding and Clotting Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Epistaxis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">1</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Vision Disorders</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Conjunctivitis</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">&lt;1</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Skin and Appendages Disorders</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> Rash</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">3</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">&lt;1</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">4</p> </td><td align="center" class="Botrule Rrule" valign="middle"> <p class="First">2</p> </td> </tr> </tbody> </table></div>

The information below includes all adverse reactions by system organ class with an incidence of 1 to < 3%, in at least one budesonide inhalation suspension treatment group where the incidence was higher with budesonide inhalation suspension than with placebo, regardless of relationship to treatment.

Blood and Lymphatic System Disorders: cervical lymphadenopathy

Ear and Labyrinth Disorders: earache

General Disorders and Administration Site Conditions: fatigue, flu-like disorder

Immune System Disorders: allergic reaction

Infections and Infestations: eye infection, herpes simplex, external ear infection, infection

Injury, Poisoning and Procedural Complication: fracture

Metabolism and Nutrition Disorders: anorexia

Musculoskeletal and Connective Tissue Disorders: myalgia

Nervous System Disorders: hyperkinesia

Psychiatric Disorders: emotional lability

Respiratory, Thoracic, and Mediastinal Disorders: chest pain, dysphonia, stridor

Skin and Subcutaneous Tissue Disorders: contact dermatitis, eczema, pustular rash, pruritus, purpura

The incidence of reported adverse events was similar between the 447 budesonide inhalation suspension-treated (mean total daily dose 0.5 to 1 mg) and 223 conventional therapy-treated pediatric asthma patients followed for one year in three open-label studies.

The following adverse reactions have been reported during post-approval use of budesonide inhalation suspension. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with budesonide inhalation suspension.

Endocrine Disorders: symptoms of hypocorticism and hypercorticism [see Warnings and Precautions (5.6)]

Eye Disorders: cataracts, glaucoma, increased intraocular pressure [see Warnings and Precautions (5.9)]

General Disorders and Administration Site Conditions: fever, pain

Immune System Disorders: Immediate and delayed hypersensitivity reactions including, anaphylaxis, angioedema, bronchospasm, rash, contact dermatitis, and urticaria [see Contraindications (4) and Warnings and Precautions (5.10)]

Infection and Infestation: sinusitis, pharyngitis, bronchitis

Musculoskeletal and Connective Tissue Disorders: avascular necrosis of the femoral head, osteoporosis, growth suppression

Nervous System Disorders: headache

Psychiatric Disorders: psychiatric symptoms including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, and anxiety

Respiratory, Thoracic, and Mediastinal Disorders: cough, dysphonia and throat irritation

Skin and Subcutaneous Tissue Disorders: skin bruising, facial skin irritation

Cases of growth suppression have been reported for inhaled corticosteroids including post-marketing reports for budesonide inhalation suspension [see Warnings and Precautions (5.8) and Use in Specific Populations (8.4)].

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 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 (5.12) and Clinical Pharmacology (12.3)].

Risk Summary There are no adequate well-controlled studies of budesonide inhalation suspension in pregnant women. However, there are published studies on the use of budesonide, the active ingredient in budesonide inhalation suspension, in pregnant women. In animal reproduction studies, budesonide, administered by the subcutaneous route, caused structural abnormalities, was embryocidal, and reduced fetal weights in rats and rabbits at less than the maximum recommended human daily inhalation dose (MRHDID), but these effects were not seen in rats that received inhaled doses approximately 2 times the MRHDID (see Data). Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to structural abnormalities from corticosteroid exposure than humans.

The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.

Labor or Delivery There are no well-controlled human studies that have investigated the effects of budesonide inhalation suspension during labor and delivery.

Data Human Data 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 (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 to 12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs. 3.3, respectively).

These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Animal Data In a fertility and reproduction study, male rats were subcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing and throughout the mating period. Females were dosed up until weaning of their offspring. Budesonide 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 doses 0.2 times the MRHDID (on a mcg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at a dose 0.05 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 5 mcg/kg/day).

In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6 to 18, budesonide produced fetal loss, decreased fetal weight, and skeletal abnormalities at doses 0.5 times the MRHDID (on a mcg/m 2 basis at a maternal subcutaneous dose of 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation days 6 to 15, budesonide produced similar adverse fetal effects at doses approximately 5 times the MRHDID (on a mcg/m2 basis at a maternal subcutaneous dose of 500 mcg/kg/day). In another embryo-fetal development study in pregnant rats, no structural abnormalities or embryocidal effects were seen at doses approximately 2 times the MRHDID (on a mcg/m 2 basis at maternal inhalation doses up to 250 mcg/kg/day).

In a peri-and post-natal development study, rats dosed from gestation day 15 to postpartum day 21, budesonide had no effects on delivery, but did have an effect on growth and development of offspring. Offspring survival was reduced and surviving offspring had decreased mean body weights at birth and during lactation at doses less than 0.2 times the MRHDID and higher (on a mcg/m 2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Risk Summary There are no available data on the effects of budesonide inhalation suspension on the breastfed child or on milk production. Budesonide, like other inhaled corticosteroids, is present in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for budesonide inhalation suspension and any potential adverse effects on the breastfed infant from budesonide inhalation suspension or from the underlying maternal condition.

Data Human data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology (12.3)].

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 (12.2), and Adverse Reactions (6.1)].

A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of 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 budesonide inhalation suspension versus placebo. However, on an individual basis, 7 patients in this study (6 in the 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 (12.2)]. Pneumonia was observed more frequently in patients treated with budesonide inhalation suspension than in patients treated with placebo, (N = 2, 1, and 0) in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo groups, respectively.

A dose dependent effect on growth was also noted in this 12 week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the budesonide inhalation suspension 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and budesonide inhalation suspension 0.5 mg of 0.2 cm (-0.6 to 1.0) and between placebo and budesonide inhalation suspension 1 mg of 0.6 cm (-0.2 to 1.4). These findings support that the use of budesonide inhalation suspension in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately one centimeter per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA)-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

In a study of asthmatic children 5 to 12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of four years, children treated with the budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study. The growth of pediatric patients receiving inhaled corticosteroids, including 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 budesonide inhalation suspension, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2) and Warnings and Precautions (5.8)].

Of the 215 patients in 3 clinical trials of budesonide inhalation suspension in adult patients, 65 (30%) were 65 years of age or older, while 22 (10%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.

Formal pharmacokinetic studies using budesonide inhalation suspension have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.

The potential for acute toxic effects following overdose of 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 (5.6)].

{ "type": "p", "children": [], "text": "The potential for acute toxic effects following overdose of 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 \n [see \n Warnings and Precautions (5.6)]. \n \n" }

Budesonide, the active component of budesonide inhalation suspension, 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 25H 34O 6 and its molecular weight is 430.5. Its structural formula is:

{ "type": "p", "children": [], "text": "Budesonide, the active component of budesonide inhalation suspension, is a corticosteroid designated chemically as (\n 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\n 25H\n 34O\n 6 and its molecular weight is 430.5. Its structural formula is:\n " }

Budesonide is 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.

{ "type": "p", "children": [], "text": "Budesonide is 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\n 3.\n " }

Budesonide inhalation suspension is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous and water for injection. It is available in single-dose ampules: 0.5 mg per 2 mL ampule. For budesonide inhalation suspension, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, under in vitro conditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. Budesonide inhalation suspension should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces [see Dosage and Administration (2)].

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is a sterile suspension for inhalation via jet nebulizer and contains the active ingredient budesonide (micronized), and the inactive ingredients anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous and water for injection. It is available in single-dose ampules: 0.5 mg per 2 mL ampule. For budesonide inhalation suspension, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari-LC-Jet Plus Nebulizer/Pari Master compressor system, under \n in vitro conditions, the mean delivered dose at the mouthpiece (% nominal dose) was approximately 17% at a mean flow rate of 5.5 L/min. The mean nebulization time was 5 minutes or less. Budesonide inhalation suspension should be administered from jet nebulizers at adequate flow rates, via face masks or mouthpieces \n [see \n Dosage and Administration (2)]. \n \n" }

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 clinical significance of these findings is unknown.

The activity of budesonide inhalation suspension 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., histamine, 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 anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85 to 95%) and the low potency of metabolites (see below).

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.

Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks.

Budesonide administered via a dry powder inhaler has been shown in various challenge models (including histamine, methacholine, sodium metabisulfite, and adenosine 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 allergen challenge.

HPA Axis Effects The effects of 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 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 budesonide inhalation suspension 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 budesonide inhalation suspension or placebo once daily. A total of 28, 17, and 31 patients in the 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 budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0.5 mg, 2 of whom received 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 budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L.

The effects of budesonide inhalation suspension at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The two higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43 to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.

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 Precautions (5.5)].

Absorption In asthmatic children 4 to 6 years of age, the total absolute bioavailability (i.e., lung + oral) following administration of 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 C max, is similar for young children and adults after inhalation of the same dose of budesonide inhalation suspension.

Distribution In asthmatic children 4 to 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 to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. 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 difference between the in vitro 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 to 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 (8.3)].

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 (5.12) and Drug Interactions (7.1)].

Cimetidine At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

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 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately 0.2 and 0.04 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis) and in female rats at oral doses up to 50 mcg/kg (approximately 0.5 and 0.1 times, respectively, MRHDID in adults and children 12 months to 8 years of age 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 (approximately 0.5 and 0.1 times, respectively, MRHDID in adults and children 12 months to 8 years of age 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 (approximately 0.5 and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.

In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately equivalent to and 0.1 times, respectively, the MRHDID in adults and children 12 months to 8 years of age 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.

Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg approximately equivalent to the MRHDID in adults on a mcg/m 2 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 MRHDID in adults on a mcg/m 2 basis. No such effects were noted at 5 mcg/kg (approximately 0.05 times the MRHDID in adults on a mcg/m 2 basis).

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 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 to 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 to 3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization). The double-blind treatment period was defined as the mean over 12 week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U.S. studies.

{ "type": "p", "children": [], "text": "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 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 to 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 to 3) as recorded in the patient diaries. Baseline was defined as the mean of the last seven days prior to randomization). The double-blind treatment period was defined as the mean over 12 week treatment period. Each of the five doses discussed below were studied in one or two, but not all three of the U.S. studies." }

Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25 mg to 0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at budesonide inhalation suspension doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily compared to placebo. Use of budesonide inhalation suspension resulted in statistically significant decreases in either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0.5 mg once daily (one study). Symptom reduction in response to budesonide inhalation suspension occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of budesonide inhalation suspension studied.

{ "type": "p", "children": [], "text": "Results of the 3 controlled clinical trials for recommended dosages of budesonide inhalation suspension (0.25 mg to 0.5 mg once or twice daily, or 1 mg once daily, up to a total daily dose of 1 mg) in 946 patients, 12 months to 8 years of age, are presented below. Statistically significant decreases in nighttime and daytime symptom scores of asthma were observed at budesonide inhalation suspension doses of 0.25 mg once daily (one study), 0.25 mg twice daily, and 0.5 mg twice daily compared to placebo. Use of budesonide inhalation suspension resulted in statistically significant decreases in either nighttime or daytime symptom scores, but not both, at doses of 1 mg once daily, and 0.5 mg once daily (one study). Symptom reduction in response to budesonide inhalation suspension occurred across gender and age. Statistically significant reductions in the need for bronchodilator therapy were also observed at all the doses of budesonide inhalation suspension studied." }

Improvements in lung function were associated with budesonide inhalation suspension in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV 1 [budesonide inhalation suspension 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [budesonide inhalation suspension 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo.

{ "type": "p", "children": [], "text": "Improvements in lung function were associated with budesonide inhalation suspension in the subgroup of patients capable of performing lung function testing. Statistically significant increases were seen in FEV\n 1 [budesonide inhalation suspension 0.5 mg once daily and 1 mg once daily (one study); 0.5 mg twice daily] and morning PEF [budesonide inhalation suspension 1 mg once daily (one study); 0.25 mg twice daily; 0.5 mg twice daily] compared to placebo.\n " }

A numerical reduction in nighttime and daytime symptom scores (0 to 3 scale) of asthma was observed within 2 to 8 days, although maximum benefit was not achieved for 4 to 6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials.

{ "type": "p", "children": [], "text": "A numerical reduction in nighttime and daytime symptom scores (0 to 3 scale) of asthma was observed within 2 to 8 days, although maximum benefit was not achieved for 4 to 6 weeks after starting treatment. The reduction in nighttime and daytime asthma symptom scores was maintained throughout the 12 weeks of the double-blind trials." }

Patients Not Receiving Inhaled Corticosteroid Therapy The efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with budesonide inhalation suspension compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.

{ "type": "p", "children": [], "text": "\nPatients Not Receiving Inhaled Corticosteroid Therapy\n\nThe efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 1. Nighttime asthma symptom scores showed statistically significant decreases in the patients treated with budesonide inhalation suspension compared to placebo. Similar decreases were also observed for daytime asthma symptom scores.\n " }

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 to 3).

{ "type": "p", "children": [], "text": "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 to 3)." }

Figure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry.

{ "type": "p", "children": [], "text": "\nFigure 1: A 12-Week Trial in Pediatric Patients Not on Inhaled Corticosteroid Therapy Prior to Study Entry.\n" }

Patients Previously Maintained on Inhaled Corticosteroids The efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with budesonide inhalation suspension compared to placebo. Similar decrease were also observed for daytime asthma symptom scores.

{ "type": "p", "children": [], "text": "\nPatients Previously Maintained on Inhaled Corticosteroids\n\nThe efficacy of 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\n 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 to 12 in nighttime asthma symptom scores are shown in Figure 2. Nighttime asthma symptom scores showed statistically significant decreases in patients treated with budesonide inhalation suspension compared to placebo. Similar decrease were also observed for daytime asthma symptom scores.\n " }

Statistically significant increases in FEV 1 compared to placebo were observed with 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).

{ "type": "p", "children": [], "text": "Statistically significant increases in FEV\n 1 compared to placebo were observed with 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).\n " }

Figure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry.

{ "type": "p", "children": [], "text": "\nFigure 2: A 12-Week Trial in Pediatric Patients Previously Maintained on Inhaled Corticosteroid Therapy Prior to Study Entry.\n" }

Patients Receiving Once-Daily or Twice-Daily Dosing The efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 3. Budesonide inhalation suspension 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.

{ "type": "p", "children": [], "text": "\nPatients Receiving Once-Daily or Twice-Daily Dosing\n\nThe efficacy of 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 to 12 in nighttime asthma symptom scores are shown in Figure 3. Budesonide inhalation suspension 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.\n " }

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.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension at a dose of 0.5 mg twice daily resulted in statistically significant increases compared to placebo in FEV\n 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.\n " }

The evidence supports the efficacy of the same nominal dose of 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 (2)].

{ "type": "p", "children": [], "text": "The evidence supports the efficacy of the same nominal dose of 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 \n [see \n Dosage and Administration (2)]. \n \n" }

Figure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry.

{ "type": "p", "children": [], "text": "\nFigure 3: A 12-Week Trial in Pediatric Patients Either Maintained on Bronchodilators Alone or Inhaled Corticosteroid Therapy Prior to Study Entry.\n" }

Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one single-dose ampule. There are 30 ampules in a carton. Each single-dose ampule contains 2 mL of white to off-white sterile liquid suspension.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one single-dose ampule.\n \nThere are 30 ampules in a carton. Each single-dose ampule contains 2 mL of white to off-white sterile liquid suspension.\n " }

Budesonide inhalation suspension is available as a single strength, containing 0.5 mg/2 mL: Unit dose packages of 30 per carton/1 ampule per foil pouch NDC 60687-524-83

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension is available as a single strength, containing 0.5 mg/2 mL:\n \nUnit dose packages of 30 per carton/1 ampule per foil pouch NDC 60687-524-83\n " }

FOR YOUR PROTECTION: Do not use if ampule appears damaged.

{ "type": "p", "children": [], "text": "\nFOR YOUR PROTECTION: Do not use if ampule appears damaged.\n " }

Budesonide inhalation suspension should be stored upright at controlled room temperature 20 to 25°C (68 to 77°F) [see USP], and protected from light. When an envelope has been opened, the shelf life of the unused ampules is 2 weeks when protected. After opening the aluminum foil envelope, the unused ampules should be returned to the aluminum foil envelope to protect them from light. Any opened ampule must be used promptly. Gently shake the ampule using a circular motion before use. Keep out of reach of children. Do not freeze.

{ "type": "p", "children": [], "text": "Budesonide inhalation suspension should be stored upright at controlled room temperature 20 to 25°C (68 to 77°F) [see USP], and protected from light. When an envelope has been opened, the shelf life of the unused ampules is 2 weeks when protected. After opening the aluminum foil envelope, the unused ampules should be returned to the aluminum foil envelope to protect them from light. Any opened ampule must be used promptly. Gently shake the ampule using a circular motion before use. Keep out of reach of children. Do not freeze." }

Patients should be advised that 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 budesonide inhalation suspension and, therefore, are not recommended. The effects of mixing budesonide inhalation suspension with other nebulizable medications have not been adequately assessed. Budesonide inhalation suspension should be administered separately in the nebulizer [see Dosage and Administration (2)].

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 budesonide inhalation suspension, but at times therapy with budesonide inhalation suspension may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.1)].

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 beta 2-agonist such as albuterol. (The healthcare professional should provide that patient with such medication and instruct the patient in how it should be used.) Patients should be instructed to notify their healthcare professional immediately if they experience any of the following:

Patients should not stop therapy with budesonide inhalation suspension without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2)].

Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of budesonide inhalation suspension. Discontinue budesonide inhalation suspension if such reactions occur [see Contraindications (4), Warning and Precautions (5.3)].

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 (5.4)].

Patients should be advised that 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 budesonide inhalation suspension [see Warnings and Precautions (5.6)].

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 (5.7)].

Patients should be informed that orally inhaled corticosteroids, including 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 (5.8)].

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 (5.9)].

Patients should be advised to use budesonide inhalation suspension at regular intervals once or twice a day, since its effectiveness depends on regular use. Maximum benefit may not be achieved for 4 to 6 weeks or longer after starting treatment. If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their healthcare professional.

See accompanying Patient Information and Instructions for Use.

LUPIN and the are registered trademarks of Lupin Pharmaceuticals, Inc.

American Health Packaging unit dose ampules (see How Supplied/Storage and Handling section) contain drug product from Lupin Pharmaceuticals, Inc. as follows: (0.5 mg per 2 mL / 30 UD) NDC 60687-524-83 packaged from NDC 68180-984

{ "type": "p", "children": [], "text": "American Health Packaging unit dose ampules (see \n How Supplied/Storage and Handling section) contain drug product from Lupin Pharmaceuticals, Inc. as follows:\n \n(0.5 mg per 2 mL / 30 UD) NDC 60687-524-83 packaged from NDC 68180-984\n " }

Distributed by: American Health Packaging Columbus, OH 43217

{ "type": "p", "children": [], "text": "Distributed by:\n \nAmerican Health Packaging\n\nColumbus, OH 43217\n " }

8452483/0525F

{ "type": "p", "children": [], "text": "\n8452483/0525F\n" }

Read the Patient Information that comes with budesonide inhalation suspension before your child starts using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your child's medical condition or treatment. If you have any questions about budesonide inhalation suspension, ask your healthcare provider or pharmacist.

What is budesonide inhalation suspension? Budesonide inhalation suspension is an inhaled corticosteroid medicine. Budesonide inhalation suspension is a long-term maintenance medicine used to control and prevent asthma symptoms in children ages 12 months to 8 years.

Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms. Budesonide inhalation suspension helps reduce swelling and inflammation in the lungs, and helps keep the airways open to reduce asthma symptoms.

Budesonide inhalation suspension does not treat the sudden symptoms (wheezing, cough, shortness of breath, and chest pain or tightness) of an asthma attack. Always have a short-acting beta 2-agonist medicine (rescue inhaler) with you to treat sudden symptoms. If your child does not have an inhaled, short-acting bronchodilator, ask your healthcare provider to have one prescribed for your child.

It is not known if budesonide inhalation suspension is safe or effective in children younger than 12 months or older than 8 years.

Who should not use budesonide inhalation suspension? Do not use budesonide inhalation suspension:

What should I tell my healthcare provider before using budesonide inhalation suspension? Before your child uses budesonide inhalation suspension, tell your healthcare provider if your child:

Budesonide inhalation suspension may not be right for children who have had any of these types of infections.

Tell your healthcare provider about all the medicine your child takes, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Using budesonide inhalation suspension with certain other medicines may affect each other causing side effects. Especially tell your healthcare provider if your child takes:

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines your child takes. Keep a list of them and show it to your healthcare provider and pharmacist when your child gets a new medicine.

How should I use budesonide inhalation suspension?

What are the possible side effects of budesonide inhalation suspension? Budesonide inhalation suspension may cause serious side effects including:

Call your healthcare provider or get medical help right away if your child has any of the serious side effects listed above.

The most common side effects of budesonide inhalation suspension include:

Tell your healthcare provider if your child has any side effect that bothers him or her or that does not go away.

For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

How should I store budesonide inhalation suspension?

Keep budesonide inhalation suspension and all medicines out of the reach of children.

General Information about budesonide inhalation suspension Medicines are sometimes prescribed for conditions other than those listed in a Patient Information leaflet. Do not use budesonide inhalation suspension for a condition for which it was not prescribed. Do not give budesonide inhalation suspension to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about budesonide inhalation suspension. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about budesonide inhalation suspension that is written for health professionals.

For more information about the drug product, go to www.lupinpharmaceuticals.com or call Lupin Pharmaceuticals, Inc. at 1-800-399-2561. For information on the packaging or labeling contact American Health Packaging at 1-800-707-4621.

What are the ingredients in budesonide inhalation suspension? Active ingredient: budesonide Inactive ingredients: anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous and water for injection.

PATIENT INSTRUCTIONS FOR USE

Important: Budesonide inhalation suspension is only for use with a jet nebulizer machine. Make sure you know how to use your jet nebulizer machine before your child uses budesonide inhalation suspension.

Budesonide inhalation suspension is a liquid that is turned into a mist by a nebulizer and inhaled into the lungs.

The face mask should be properly adjusted to optimize delivery and to avoid exposing the eyes to the nebulized medication. Corticosteroid effects on the skin can be avoided if the face is washed after the use of a face mask.

1. Budesonide inhalation suspension comes in a sealed protective aluminium foil envelope.

2. Gently shake the budesonide inhalation suspension ampule using a circular motion as shown in Figure 1.

Figure 1

3. Hold the budesonide inhalation suspension ampule upright without squeezing the ampule and open by twisting off the top as shown in Figure 2.

Figure 2

4. Place the open end of the budesonide inhalation suspension ampule into the nebulizer cup (reservoir) and slowly squeeze all of the medicine from the ampule into the nebulizer medicine cup as shown in Figure 3. Throw away the empty ampule.

Figure 3

5. Use your jet nebulizer as directed.

Distributed by: American Health Packaging Columbus, OH 43217

8452483/0525F

NDC 60687- 524-83

{ "type": "p", "children": [], "text": "NDC 60687-\n 524-83\n " }

Budesonide Inhalation Suspension

{ "type": "p", "children": [], "text": "\nBudesonide\n\nInhalation Suspension\n" }

0.5 mg/2 mL

{ "type": "p", "children": [], "text": "\n0.5 mg/2 mL\n" }

Rx Only FOR INHALATION ONLY

{ "type": "p", "children": [], "text": "\nRx Only\n\nFOR INHALATION ONLY\n" }

Once an Ampule is opened, use the contents immediately. For use only in a jet nebulizer. Do NOT use in an ultrasonic nebulizer.

{ "type": "p", "children": [], "text": "Once an Ampule is opened, use the contents immediately.\n \nFor use only in a jet nebulizer.\n \nDo NOT use in an ultrasonic nebulizer.\n " }

30 x 2 mL unit-dose ampules each in a foil pouch.

{ "type": "p", "children": [], "text": "\n30 x 2 mL unit-dose ampules\n\neach in a foil pouch.\n" }

Each unit-dose ampule delivers 2 mL of a sterile suspension containing 0.5 mg of micronized budesonide USP.

{ "type": "p", "children": [], "text": "Each unit-dose ampule delivers 2 mL of a sterile suspension\n \ncontaining 0.5 mg of micronized budesonide USP.\n " }

Usual Dosage: Once a foil pouch is opened, use the ampule within 2 weeks. Use as directed by physician. Follow the Patient Instructions for proper use of Budesonide Inhalation Suspension. See package insert for full prescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: Once a foil pouch is opened, use the ampule within\n \n2 weeks. Use as directed by physician. Follow the Patient\n \nInstructions for proper use of Budesonide Inhalation Suspension.\n \nSee package insert for full prescribing information.\n " }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F); excursions permitted\n\nbetween 15° to 30°C (59° to 86°F) [see USP Controlled\n \nRoom Temperature].\n \n\nDo not freeze. Protect from light.\n" }

Store unopened ampule in foil pouch placed upright in the carton.

{ "type": "p", "children": [], "text": "\nStore unopened ampule in foil pouch placed upright in\n \nthe carton.\n \n" }

Inactives: anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous and water for injection.

{ "type": "p", "children": [], "text": "\nInactives: anhydrous citric acid, disodium edetate dihydrate,\n \npolysorbate 80, sodium chloride, sodium citrate anhydrous and\n \nwater for injection.\n " }

Keep this and all drugs out of reach of children.

{ "type": "p", "children": [], "text": "\nKeep this and all drugs out of reach of children.\n" }

FOR YOUR PROTECTION: Do not use if ampule appears damaged.

{ "type": "p", "children": [], "text": "\nFOR YOUR PROTECTION:\n\nDo not use if ampule appears damaged.\n " }

The drug product contained in this package is from NDC# 68180-984, Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "The drug product contained in this package is from\n \nNDC# 68180-984, Lupin Pharmaceuticals, Inc.\n " }

Distributed by: American Health Packaging Columbus, OH 43217

{ "type": "p", "children": [], "text": "Distributed by:\n \nAmerican Health Packaging\n \nColumbus, OH 43217\n " }

5552483/0823

{ "type": "p", "children": [], "text": "5552483/0823" }

NDC 60687- 524-79

{ "type": "p", "children": [], "text": "NDC 60687-\n 524-79\n " }

Budesonide Inhalation Suspension

{ "type": "p", "children": [], "text": "\nBudesonide\n\nInhalation\n\nSuspension\n" }

0.5 mg/2 mL

{ "type": "p", "children": [], "text": "\n0.5 mg/2 mL\n" }

FOR INHALATION ONLY

{ "type": "p", "children": [], "text": "\nFOR INHALATION ONLY\n" }

Each unit-dose ampule delivers 2 mL of a sterile suspension containing 0.5 mg of micronized budesonide USP.

{ "type": "p", "children": [], "text": "Each unit-dose ampule delivers 2 mL of a sterile\n \nsuspension containing 0.5 mg of micronized\n \nbudesonide USP.\n " }

Shake gently using a circular motion prior to use. Once ampule is opened, use immediately. For use only in a jet nebulizer. Do NOT use in an ultrasonic nebulizer.

{ "type": "p", "children": [], "text": "Shake gently using a circular motion prior to\n \nuse. Once ampule is opened, use immediately.\n \nFor use only in a jet nebulizer. \n Do NOT use in an\n\nultrasonic nebulizer.\n" }

Usual Dosage: Use as directed by physician. Follow the Patient Instructions for proper use of Budesonide Inhalation Suspension. See package insert for full prescribing information.

{ "type": "p", "children": [], "text": "\nUsual Dosage: Use as directed by physician.\n \nFollow the Patient Instructions for proper use of\n \nBudesonide Inhalation Suspension. See\n \npackage insert for full prescribing information.\n " }

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light.

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F);\n\nexcursions permitted between 15° to\n\n30°C (59° to 86°F) [see USP Controlled\n\nRoom Temperature]. Do not freeze.\n\nProtect from light.\n" }

Store unopened ampule in foil pouch placed upright in the carton. Once a foil pouch is opened, use the ampule within two weeks.

{ "type": "p", "children": [], "text": "\nStore unopened ampule in foil pouch\n\nplaced upright in the carton. Once a foil\n\npouch is opened, use the ampule within\n\ntwo weeks.\n" }

Inactives: anhydrous citric acid, disodium edetate dihydrate, polysorbate 80, sodium chloride, sodium citrate anhydrous and water for injection.

{ "type": "p", "children": [], "text": "\nInactives: anhydrous citric acid,\n \ndisodium edetate dihydrate, polysorbate\n \n80, sodium chloride, sodium citrate\n \nanhydrous and water for injection.\n " }

Keep this and all drugs out of reach of children.

{ "type": "p", "children": [], "text": "\nKeep this and all drugs\n\nout of reach of children.\n" }

Rx Only

{ "type": "p", "children": [], "text": "\nRx Only\n" }

The drug product contained in this package is from NDC# 68180-984, Lupin Pharmaceuticals, Inc.

{ "type": "p", "children": [], "text": "The drug product contained in this package is from\n \nNDC# 68180-984, Lupin Pharmaceuticals, Inc.\n " }

Distributed by: American Health Packaging Columbus, OH 43217

{ "type": "p", "children": [], "text": "Distributed by:\n \nAmerican Health Packaging\n \nColumbus, OH 43217\n " }

0452483/0621

{ "type": "p", "children": [], "text": "0452483/0621" }

Budesonide extended-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis.

{ "type": "p", "children": [], "text": "Budesonide extended-release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. " }

The recommended dosage for the induction of remission in adult patients with active, mild to moderate ulcerative colitis is 9 mg taken orally once daily in the morning with or without food for up to 8 weeks. Budesonide extended-release tablets should be swallowed whole and not chewed, crushed or broken.

If concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated, patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Avoid grapefruit juice, which is known to inhibit CYP3A4, when taking budesonide extended-release tablets. In these cases, discontinuation of budesonide extended-release tablets or the CYP3A4 inhibitor should be considered [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP.

{ "type": "p", "children": [], "text": "Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP." }

{ "type": "", "children": [], "text": "" }

Budesonide extended-release tablets are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide extended-release tablets. Anaphylactic reactions have occurred with other budesonide formulations [see Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Budesonide extended-release tablets are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of budesonide extended-release tablets. Anaphylactic reactions have occurred with other budesonide formulations [see Adverse Reactions (6.2)]. " }

Systemic effects such as hypercorticism and adrenal suppression may occur with use of corticosteroids, including budesonide extended-release tablets. Monitor patients for signs and symptoms of hypercorticism and adrenal axis suppression during treatment with budesonide extended-release tablets.

Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide extended-release tablets should be considered in these patients [see Use in Specific Populations (8.6)].

Glucocorticosteroids, including budesonide extended-release tablets, can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended.

Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide extended-release tablets, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients, and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with budesonide extended-release tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Corticosteroids, including budesonide extended-release tablets, suppress the immune system and increase the risk of infection with any pathogen, including viral, bacterial, fungal, protozoan, or helminthic pathogens. Corticosteroids can:

Corticosteroid-associated infections can be mild but can be severe and at times fatal. The rate of infectious complications increases with increasing corticosteroid dosages.

Monitor patients for the development of infection and consider discontinuation of budesonide extended-release tablets if the patient develops an infection while on treatment.

Tuberculosis

If budesonide extended-release tablets are used in patients with latent tuberculosis or tuberculin reactivity, reactivation of tuberculosis may occur. Closely monitor such patients for reactivation. During prolonged budesonide extended-release tablets therapy, patients with latent tuberculosis or tuberculin reactivity should receive chemoprophylaxis.

Varicella Zoster and Measles Viral Infections

Varicella and measles can have a serious or even fatal course in non-immune patients taking corticosteroids, including budesonide extended-release tablets. In corticosteroid-treated patients who have not had these diseases or are non-immune, particular care should be taken to avoid exposure to varicella and measles:

Hepatitis B Virus Reactivation

Hepatitis B virus reactivation can occur in patients who are hepatitis B carriers treated with immunosuppressive dosages of corticosteroids, including budesonide extended-release tablets. Reactivation can also occur infrequently in corticosteroid-treated patients who appear to have resolved hepatitis B infection.

Screen patients for hepatitis B infection before initiating immunosuppressive (e.g., prolonged) treatment with budesonide extended-release tablets. For patients who show evidence of hepatitis B infection, recommend consultation with physicians with expertise in managing hepatitis B regarding monitoring and consideration for hepatitis B antiviral therapy.

Fungal Infections

Corticosteroids, including budesonide extended-release tablets, may exacerbate systemic fungal infections; therefore, avoid budesonide extended-release tablets use in the presence of such infections. For patients on chronic budesonide extended-release tablets therapy who develop systemic fungal infections, budesonide extended-release tablets withdrawal or dosage reduction is recommended.

Amebiasis

Corticosteroids, including budesonide extended-release tablets, may activate latent amebiasis. Therefore, it is recommended that latent amebiasis or active amebiasis be ruled out before initiating budesonide extended-release tablets in patients who have spent time in the tropics or patients with unexplained diarrhea.

Strongyloides Infestation

Avoid budesonide extended-release tablets in patients with known or suspected Strongyloides (threadworm) infection. Corticosteroids-induced immunosuppression may lead to Strongyloides superinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Cerebral Malaria

Avoid corticosteroids, including budesonide extended-release tablets, in patients with cerebral malaria.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement of Kaposi’s sarcoma.

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use in Specific Populations (8.6)].

Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of budesonide extended-release tablets has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1,105 patients with ulcerative colitis.

In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received budesonide extended-release tablets 9 mg, 254 patients received budesonide extended-release tablets 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean = 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with budesonide extended-release tablets 9 mg are summarized in Table 1.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 1. Summary of Adverse Reactions in Two Placebo-Controlled Trials Experienced by at Least 2% of the Budesonide Extended-Release Tablets 9 mg Group (Studies 1 and 2) </span> </caption> <col width="30%"/> <col width="28%"/> <col width="27%"/> <col width="15%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide Extended-<br/>Release Tablets 9 mg<br/>(N = 255) <br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide Extended-<br/>Release Tablets 6 mg <br/>(N = 254)<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo <br/>(N = 258)<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Headache </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">29 (11.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">37 (14.6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (10.5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Nausea </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13 (5.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 (4.7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (4.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Decreased blood cortisol </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (4.3)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Upper abdominal pain </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (3.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (1.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Fatigue </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (1.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Flatulence </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (1.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Abdominal distension </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1.6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Acne </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (1.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Urinary tract infection </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Arthralgia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Constipation </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (2.0)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td> </tr> </tbody> </table></div>

Of budesonide extended-release tablets 9 mg patients, a total of 15% discontinued treatment due to any adverse event (including adverse reactions) compared with 17% in the placebo group.

Table 2 summarizes the percentages of patients reporting glucocorticoid-related effects in the 2 placebo-controlled studies.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 2. Summary of Glucocorticoid-Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)</span> </caption> <col width="25%"/> <col width="25%"/> <col width="25%"/> <col width="25%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide <br/>Extended-Release <br/>Tablets 9 mg <br/>(N = 255)<br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide <br/>Extended-Release <br/>Tablets 6 mg <br/>(N = 254) <br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo <br/>(N = 258)<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Overall </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">26 (10.2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19 (7.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">27 (10.5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Mood changes </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9 (3.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (3.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">11 (4.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sleep changes </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 (2.7)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">10 (3.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">12 (4.7)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Insomnia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">8 (3.1)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Acne </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">6 (2.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">5 (1.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Moon face </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1.2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1.2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (1.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Fluid retention </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1.2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1.2)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Hirsutism </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Striae rubrae </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (0.8)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">   Flushing </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (1.2)</p> </td> </tr> </tbody> </table></div>

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid-related effects between budesonide extended-release tablets and placebo after 8 weeks of induction therapy.

Study 3 was an open-label study evaluating budesonide extended-release tablets 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1) but had not achieved remission. Among patients who took budesonide extended-release tablets 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took budesonide extended-release tablets 9 mg for 8 weeks in Study 1.

In Study 4, the safety of long-term treatment with budesonide extended-release tablets 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to budesonide extended-release tablets 6 mg or placebo once daily for 12 months. In patients who took budesonide extended-release tablets 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and budesonide extended-release tablets 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the budesonide extended-release tablets 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans.

In Study 4, the glucocorticoid-related effects were similar in patients with up to 12 months of therapy with budesonide extended-release tablets 6 mg and placebo (Table 3).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 3. Summary of Glucocorticoid-Related Effects Over 12-Month Treatment (Study 4) </span> </caption> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide Extended-<br/>Release Tablets 6 mg <br/>(N = 62) <br/>n (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo<br/>(N = 61)<br/>n (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Overall </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9 (14.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">7 (11.5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Insomnia </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (6.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (6.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Mood changes </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4 (6.5)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">2 (3.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Moon face </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Sleep changes </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.9)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Acne </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Hirsutism </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">3 (4.8)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">   Flushing </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (1.6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (1.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">   Fluid retention </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (1.6)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">1 (1.6)</p> </td> </tr> </tbody> </table></div>

In addition to adverse events reported from clinical trials, the following adverse reactions have been identified during post-approval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to budesonide extended-release tablets, or a combination of these factors.

Gastrointestinal Disorders: diarrhea, rectal bleeding General Disorders and Administrative Site Conditions: peripheral edema Immune System Disorders: anaphylactic reactions Musculoskeletal and Connective Tissue Disorders: muscle cramps/spasms Nervous System Disorders: benign intracranial hypertension, dizziness Psychiatric Disorders: mood swings Skin and Subcutaneous Tissue Disorders: rash Vascular Disorders: increased blood pressure

Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of budesonide extended-release tablets should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with budesonide extended-release tablets administration [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].

Since the dissolution of the coating of budesonide extended-release tablets is pH dependent, the release properties and uptake of the compound may be altered when budesonide extended-release tablets are used after treatment with gastric acid reducing agents (e.g., proton pump inhibitors (PPIs), H2 blockers and antacids).

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 0.5 times and 0.05 times, respectively, the maximum recommended human dose, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)].

Budesonide was teratogenic and embryolethal in rabbits and rats. In an embryofetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). In an embryofetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.01 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis).

In a peri- and postnatal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.02 times the MRHD (on a mg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Lactation studies have not been conducted with budesonide extended-release tablets or other oral budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide extended-release tablets and any potential adverse effects on the breastfed infant from budesonide extended-release tablets, or from the underlying maternal condition.

One published study reports that budesonide is present in human milk following maternal inhalation of budesonide which resulted in infant doses approximately 0.3% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The recommended daily dose of budesonide extended-release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 mcg daily) given to mothers in the above described study.

The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5 to 10 nmol/L which is up to 10 times higher than the 1 to 2 nmol/L for a 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of budesonide extended-release tablets, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation.

Safety and effectiveness of budesonide extended-release tablets in pediatric patients have not been established. Glucocorticosteroids, such as budesonide extended-release tablets, may cause a reduction of growth velocity in pediatric patients.

Clinical studies of budesonide extended-release tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, budesonide extended-release tablets should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide extended-release tablets should be considered in these patients [see Warnings and Precautions (5.5)].

Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy.

{ "type": "p", "children": [], "text": "Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. " }

If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily.

{ "type": "p", "children": [], "text": "If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects, such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily." }

Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema.

{ "type": "p", "children": [], "text": "Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. " }

Budesonide extended-release tablets, for oral administration, contain budesonide, a synthetic corticosteroid, as the active ingredient. Budesonide is designated chemically as (R,S)-11ß,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dionecyclic-16,17-acetal with butyraldehyde.

{ "type": "p", "children": [], "text": "Budesonide extended-release tablets, for oral administration, contain budesonide, a synthetic corticosteroid, as the active ingredient. Budesonide is designated chemically as (R,S)-11ß,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dionecyclic-16,17-acetal with butyraldehyde." }

Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.53. Its structural formula is:

{ "type": "p", "children": [], "text": "Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.53. Its structural formula is: " }

Budesonide, USP is a white or almost white crystalline odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform.

{ "type": "p", "children": [], "text": "Budesonide, USP is a white or almost white crystalline odorless powder that is practically insoluble in water, sparingly soluble in alcohol, and freely soluble in chloroform." }

Budesonide, a delayed and extended-release tablet, is coated with a polymer film, which breaks down at or above pH 7. The tablet core contains budesonide with polymers that provide for extended release of budesonide.

{ "type": "p", "children": [], "text": "Budesonide, a delayed and extended-release tablet, is coated with a polymer film, which breaks down at or above pH 7. The tablet core contains budesonide with polymers that provide for extended release of budesonide. " }

Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and type B, microcrystalline cellulose, polyethylene glycol, polydextrose, talc, titanium dioxide, triacetin and triethyl citrate.

{ "type": "p", "children": [], "text": "Each tablet contains the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and type B, microcrystalline cellulose, polyethylene glycol, polydextrose, talc, titanium dioxide, triacetin and triethyl citrate. " }

In addition, the black imprinting ink contains black iron oxide, hypromellose and propylene glycol.

{ "type": "p", "children": [], "text": "In addition, the black imprinting ink contains black iron oxide, hypromellose and propylene glycol." }

Budesonide has a high topical glucocorticosteroid (GCS) activity and substantial first-pass elimination. The formulation contains budesonide in an extended-release tablet core. The tablet core is enteric coated to protect dissolution in gastric juice which delays budesonide release until exposure to a pH ≥ 7 in the small intestine. Upon disintegration of the coating, the core matrix provides extended release of budesonide in a time dependent manner.

Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect, and the affinity of budesonide to GCS receptors, which reflects the intrinsic potency of the drug, is about 200-fold that of cortisol and 15-fold that of prednisolone.

Treatment with systemically active GCS, including budesonide extended-release tablets, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function. Markers, indirect and direct, of this are cortisol levels in plasma or urine and response to ACTH stimulation.

In a study assessing the response to ACTH stimulation test in patients treated with budesonide extended-release tablets 9 mg once daily, the proportion of patients with abnormal response was 47% at 4 weeks and 79% at 8 weeks.

Following single oral administration of budesonide extended-release tablets 9 mg in healthy subjects, peak plasma concentration (Cmax) was 1.35 ± 0.96 ng/mL, the time to peak concentration (Tmax) on average was 13.3 ± 5.9 hours, although it varied across different individual patients, and the area under the plasma concentration time curve (AUC) was approximately 16.43 ± 10.52 ng•hr/mL. The pharmacokinetic parameters of budesonide extended-release tablets 9 mg have a high degree of variability among subjects. There was no accumulation of budesonide with respect to both AUC and Cmax following 7 days of budesonide extended-release tablets 9 mg once daily dosing.

A food-effect study involving administration of budesonide extended-release tablets to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by 27% while there was no significant decrease in AUC. Additionally, a mean delay in absorption lag time of 2.4 hours was observed under fed conditions.

The mean volume of distribution (VSS) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is about 0.8.

Following absorption, budesonide is subject to high first-pass metabolism (80-90%). In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (< 1/100) in relation to that of the parent compound.

In vivo investigations with intravenous doses in healthy subjects are in agreement with the in vitro findings and demonstrate that budesonide has a high plasma clearance, 0.9-1.8 L/min. These high plasma clearance values approach the estimated liver blood flow, and, accordingly, suggest that budesonide is a high hepatic clearance drug.

The plasma elimination half-life, t1/2, after administration of intravenous doses ranges between 2 and 3.6 hours.

Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxy budesonide and 16α-hydroxy prednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.

The pharmacokinetics of budesonide in patients with renal impairment have not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide (< 1/100).

In patients with liver cirrhosis, systemic availability of orally administered budesonide correlates with disease severity and is, on average, 2.5-fold higher compared with healthy controls. Patients with mild liver disease are minimally affected. Patients with severe liver dysfunction were not studied. Absorption parameters were not altered, and for the intravenous dose, no significant differences in CL or VSS were observed.

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fold increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels [see Dosage and Administration (2) and Drug Interactions (7)].

Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels of oral contraceptives (i.e., ethinyl estradiol).

Carcinogenicity studies with budesonide were conducted in rats and mice. 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 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis).

Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocycte unscheduled DNA synthesis (UDS) test and the mouse micronucleus test.

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

Induction of Remission in Active, Mild to Moderate Ulcerative Colitis

{ "type": "p", "children": [], "text": "\nInduction of Remission in Active, Mild to Moderate Ulcerative Colitis \n" }

Two similarly designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of ≥ 4 and ≤ 10). Eight hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease activity (score of 0 to 3 for each of the components).

{ "type": "p", "children": [], "text": "Two similarly designed, randomized, double-blind, placebo-controlled studies were conducted in a total of 970 adult patients with active, mild to moderate ulcerative colitis (UC) which was defined as an Ulcerative Colitis Disease Activity Index (UCDAI of ≥ 4 and ≤ 10). Eight hundred ninety-nine of these patients had histology consistent with active UC; this was considered the primary analysis population. UCDAI is a four-component scale (total score of 0 to 12) that encompasses the clinical assessments of stool frequency, rectal bleeding, mucosal appearance and physician’s rating of disease activity (score of 0 to 3 for each of the components). " }

The baseline median UCDAI score in both studies was 7.

{ "type": "p", "children": [], "text": "The baseline median UCDAI score in both studies was 7. " }

In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years. In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian.

{ "type": "p", "children": [], "text": "In Study 1, 56% of patients were male, and the median age was 42 years. In Study 2, 57% of patients were male, and the median age was 44 years. In Study 1, 50% of patients were Caucasian, 7% were African American, and 34% were Asian. In Study 2, more than 99% were Caucasian." }

Both studies compared budesonide extended-release tablets 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1 and a budesonide* 9 mg not approved for the treatment of UC in Study 2). The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤ 1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥ 1 point reduction in an endoscopy-only score. In both studies, budesonide 9 mg extended-release tablets demonstrated superiority to placebo in inducing remission (Table 4).

{ "type": "p", "children": [], "text": "Both studies compared budesonide extended-release tablets 9 mg and 6 mg with placebo and included an active reference arm (a mesalamine 2.4 g in Study 1 and a budesonide* 9 mg not approved for the treatment of UC in Study 2). The primary endpoint was induction of remission after 8 weeks of treatment. Remission was defined as a UCDAI score of ≤ 1, with subscores of 0 for rectal bleeding, stool frequency, and mucosal appearance and with a ≥ 1 point reduction in an endoscopy-only score. In both studies, budesonide 9 mg extended-release tablets demonstrated superiority to placebo in inducing remission (Table 4)." }

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Table 4. Induction of Remission in Studies 1 and 2 Treatment Group</span> </caption> <col width="50%"/> <col width="25%"/> <col width="25%"/> <tfoot> <tr> <td align="left" colspan="3" valign="top">The primary analysis population included only patients that had histology consistent with active UC. </td> </tr> <tr> <td align="left" colspan="3" valign="top">CI = Confidence Interval </td> </tr> <tr> <td align="left" colspan="3"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC. </dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>p &lt; 0.025 for budesonide extended-release tablets 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha = 0.025)</dd> </dl> </td> </tr> </tfoot> <tbody class="Headless"> <tr> <td class="Botrule Lrule Rrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Treatment Group</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Study 1<br/>n/N (%)</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Study 2<br/>n/N (%)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Budesonide Extended-Release Tablets 9 mg </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">22/123 (17.9)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">19/109 (17.4)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Budesonide Extended-Release Tablets 6 mg </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">16/121 (13.2)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9/109 (8.3)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Reference arm<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">15/124 (12.1)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">13/103 (12.6)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First">Placebo </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">9/121 (7.4)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">4/89 (4.5)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First">Treatment difference between budesonide extended-release tablets 9 mg and placebo (95% CI)<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">10.4% (2.2%, 18.7%)</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12.9% (4.6%, 21.3%)</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table class=\"Noautorules\" width=\"100%\">\n<caption>\n<span>Table 4. \tInduction of Remission in Studies 1 and 2 Treatment Group</span>\n</caption>\n<col width=\"50%\"/>\n<col width=\"25%\"/>\n<col width=\"25%\"/>\n<tfoot>\n<tr>\n<td align=\"left\" colspan=\"3\" valign=\"top\">The primary analysis population included only patients that had histology consistent with active UC. </td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"3\" valign=\"top\">CI = Confidence Interval </td>\n</tr>\n<tr>\n<td align=\"left\" colspan=\"3\">\n<dl class=\"Footnote\">\n<dt>\n<a href=\"#footnote-reference-1\" name=\"footnote-1\">*</a>\n</dt>\n<dd>The reference arm in Study 1 is a delayed release mesalamine 2.4 g; the reference arm in Study 2 is a budesonide 9 mg not approved for the treatment of UC. </dd>\n<dt>\n<a href=\"#footnote-reference-2\" name=\"footnote-2\">†</a>\n</dt>\n<dd>p &lt; 0.025 for budesonide extended-release tablets 9 mg vs. placebo in both Studies 1 and 2 based on the Chi-square test (alpha = 0.025)</dd>\n</dl>\n</td>\n</tr>\n</tfoot>\n<tbody class=\"Headless\">\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"bottom\">\n<p class=\"First\">\n<span class=\"Bold\">Treatment Group</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Study 1<br/>n/N (%)</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Study 2<br/>n/N (%)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Budesonide Extended-Release Tablets 9 mg </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">22/123 (17.9)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">19/109 (17.4)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Budesonide Extended-Release Tablets 6 mg </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">16/121 (13.2)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">9/109 (8.3)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Reference arm<a class=\"Sup\" href=\"#footnote-1\" name=\"footnote-reference-1\">*</a>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">15/124 (12.1)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">13/103 (12.6)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">Placebo </p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">9/121 (7.4)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">4/89 (4.5)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">Treatment difference between budesonide extended-release tablets 9 mg and placebo (95% CI)<a class=\"Sup\" href=\"#footnote-2\" name=\"footnote-reference-2\">†</a>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">10.4% (2.2%, 18.7%)</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">12.9% (4.6%, 21.3%)</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

{ "type": "", "children": [], "text": "" }

Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP.

{ "type": "p", "children": [], "text": "Budesonide Extended-Release Tablets are available containing 9 mg of budesonide, USP." }

The 9 mg tablets are white, film-coated, round, unscored tablets with M over BE9 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:

{ "type": "p", "children": [], "text": "The 9 mg tablets are white, film-coated, round, unscored tablets with M over BE9 imprinted in black ink on one side of the tablet and blank on the other side. They are available as follows:" }

NDC 0378-4500-93bottles of 30 tablets

{ "type": "p", "children": [], "text": "NDC 0378-4500-93bottles of 30 tablets" }

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]\n" }

Keep container tightly closed. Protect from light and moisture.

{ "type": "p", "children": [], "text": "\nKeep container tightly closed. Protect from light and moisture.\n" }

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure." }

Advise the patient to read the FDA-approved patient labeling (Patient Information).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information)." }

Patients treated with budesonide extended-release tablets should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of budesonide extended-release tablets.

{ "type": "p", "children": [], "text": "Patients treated with budesonide extended-release tablets should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of budesonide extended-release tablets." }

Hypercorticism and Adrenal Suppression Advise patients that budesonide extended-release tablets may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Taper slowly from systemic corticosteroids if transferring to budesonide extended-release tablets [see Warnings and Precautions (5.1) and (5.2)].

{ "type": "p", "children": [], "text": "\nHypercorticism and Adrenal Suppression \nAdvise patients that budesonide extended-release tablets may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Taper slowly from systemic corticosteroids if transferring to budesonide extended-release tablets [see Warnings and Precautions (5.1) and (5.2)]. " }

Immunosuppression and Increased Risk of Infection Advise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients to inform their healthcare provider if they are exposed to varicella or measles or develop a new or worsening infection [(see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "\nImmunosuppression and Increased Risk of Infection \nAdvise patients to avoid exposure to people with varicella (chicken pox) or measles. Advise patients to inform their healthcare provider if they are exposed to varicella or measles or develop a new or worsening infection [(see Warnings and Precautions (5.3)]. " }

Kaposi’s Sarcoma Advise patients that Kaposi’s sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi’s sarcoma [see Warnings and Precautions (5.4)].

{ "type": "p", "children": [], "text": "\nKaposi’s Sarcoma\nAdvise patients that Kaposi’s sarcoma has been reported in patients receiving corticosteroids for chronic conditions and to inform their healthcare provider if they experience signs or symptoms of Kaposi’s sarcoma [see Warnings and Precautions (5.4)].\n" }

How to Take Budesonide Extended-Release Tablets Advise patients to swallow budesonide extended-release tablets whole with water. Do not chew or crush. Avoid the consumption of grapefruit juice for the duration of budesonide extended-release tablets therapy [see Dosage and Administration (2)].

{ "type": "p", "children": [], "text": "\nHow to Take Budesonide Extended-Release Tablets \nAdvise patients to swallow budesonide extended-release tablets whole with water. Do not chew or crush. Avoid the consumption of grapefruit juice for the duration of budesonide extended-release tablets therapy [see Dosage and Administration (2)]. " }

Pregnancy Advise female patients that budesonide extended-release tablets may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "\nPregnancy \nAdvise female patients that budesonide extended-release tablets may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Budesonide Extended-Release Tablets</span> </p> <p> <span class="Bold">(bue desʹ oh nide)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are budesonide extended-release tablets? </span> </p> <dl> <dt>•</dt> <dd>Budesonide extended-release tablets are a prescription corticosteroid medicine used to help get active mild to moderate ulcerative colitis (UC) under control (induce remission). </dd> <dt>•</dt> <dd>It is not known if budesonide extended-release tablets are safe and effective in children. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Who should not take budesonide extended-release tablets? </span> </p> <p>Do not take budesonide extended-release tablets if: </p> <dl> <dt>•</dt> <dd>you are allergic to budesonide or any of the ingredients in budesonide extended-release tablets. See the end of this leaflet for a complete list of ingredients in budesonide extended-release tablets. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before taking budesonide extended-release tablets? </span> </p> <p> <span class="Bold">Before you take budesonide extended-release tablets tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have liver problems. </dd> <dt>•</dt> <dd>are planning to have surgery.</dd> <dt>•</dt> <dd>have chickenpox or measles or have recently been near anyone with chickenpox or measles.</dd> <dt>•</dt> <dd>have an infection, including fungal and threadworm (<span class="Italics">Strongyloides</span>) infections.</dd> <dt>•</dt> <dd>have or had a family history of diabetes, cataracts or glaucoma.</dd> <dt>•</dt> <dd>have or had tuberculosis.</dd> <dt>•</dt> <dd>have high blood pressure (hypertension).</dd> <dt>•</dt> <dd>have decreased bone mineral density (osteoporosis).</dd> <dt>•</dt> <dd>have stomach ulcers.</dd> <dt>•</dt> <dd>have malaria of the brain (cerebral malaria).</dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. Budesonide extended-release tablets may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide extended-release tablets or breastfeed. You should not do both. </dd> </dl> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide extended-release tablets and other medicines may affect each other causing side effects.</p> <p>Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I take budesonide extended-release tablets? </span> </p> <dl> <dt>•</dt> <dd>Take budesonide extended-release tablets exactly as your healthcare provider tells you to take them. </dd> <dt>•</dt> <dd>Take budesonide extended-release tablets 1 time each day in the morning with or without food. </dd> <dt>•</dt> <dd>Take budesonide extended-release tablets whole with water. Do not chew, crush, or break budesonide extended-release tablets before swallowing. </dd> <dt>•</dt> <dd>If you take too many budesonide extended-release tablets, call your healthcare provider right away or go to the nearest hospital emergency room. </dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What should I avoid while taking budesonide extended-release tablets? </span> </p> <dl> <dt>•</dt> <dd>Do not eat grapefruit or drink grapefruit juice while taking budesonide extended-release tablets. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide in your blood. </dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of budesonide extended-release tablets? </span> </p> <p>Budesonide extended-release tablets may cause serious side effects, including:</p> <dl> <dt>•</dt> <dd> <span class="Bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism). </span>Long-time use of budesonide extended-release tablets can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: <dl> <dt>o</dt> <dd>acne </dd> <dt>o</dt> <dd>bruise easily </dd> <dt>o</dt> <dd>rounding of your face (moon face) </dd> <dt>o</dt> <dd>ankle swelling </dd> <dt>o</dt> <dd>thicker or more hair on your body and face </dd> <dt>o</dt> <dd>a fatty pad or hump between your shoulders (buffalo hump) </dd> <dt>o</dt> <dd>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Adrenal suppression. </span>When budesonide extended-release tablets are taken for a long period of time (chronic use), the adrenal glands do not make enough steroid hormones (adrenal suppression). <br/>Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide extended-release tablets including: </dd> </dl> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>tiredness</dd> <dt>o</dt> <dd>weakness</dd> <dt>o</dt> <dd>nausea</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>vomiting</dd> <dt>o</dt> <dd>low blood pressure</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <dl> <dt>•</dt> <dd> <span class="Bold">Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection.<br/> </span>Corticosteroid medicines, including budesonide extended-release tablets, lower the ability of your immune system to fight infections and increase the risk of infections caused by viruses, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines, including budesonide extended-release tablets, can also:<dl> <dt>o</dt> <dd>make current infections worse</dd> <dt>o</dt> <dd>increase the risk of infections spreading (disseminated)</dd> <dt>o</dt> <dd>increase the risk of making infections active again or making infections worse that have not been active (latent)</dd> <dt>o</dt> <dd>hide (mask) some signs of infection</dd> </dl> </dd> </dl> <p class="First">These infections can be mild but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide extended-release tablets. Tell you healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide extended-release tablets, including flu-like symptoms such as:</p> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>o</dt> <dd>fever</dd> <dt>o</dt> <dd>chills</dd> <dt>o</dt> <dd>stomach area (abdominal)<br/>pain</dd> <dt>o</dt> <dd>aches</dd> <dt>o</dt> <dd>diarrhea</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>o</dt> <dd>cough</dd> <dt>o</dt> <dd>pain</dd> <dt>o</dt> <dd>feeling tired</dd> <dt>o</dt> <dd>nausea and vomiting</dd> </dl> </td> </tr> <tr> <td class="Lrule Rrule" colspan="2" valign="top"> <dl> <dt> </dt> <dd> <dl> <dt>o</dt> <dd>Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide extended-release tablets. Your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide extended-release tablets. </dd> <dt>o</dt> <dd>Chickenpox and measles: People taking corticosteroid medicines, including budesonide extended-release tablets, who have not had chickenpox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chickenpox or measles. </dd> <dt>o</dt> <dd>Hepatitis B virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide extended-release tablets. Your healthcare provider will test you for HBV before you start taking budesonide extended-release tablets. </dd> <dt>o</dt> <dd>Amebiasis: Inactive (latent) amebiasis may become an active infection while taking budesonide extended-release tablets. Your healthcare provider should check you for amebiasis before you start taking budesonide extended-release tablets in people who have spent time in the tropics or have unexplained diarrhea. </dd> </dl> </dd> <dt>•</dt> <dd>Kaposi’s sarcoma. Kaposi’s sarcoma has happened in people who received corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions.</dd> <dt>•</dt> <dd>Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide extended-release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended-release tablets.</dd> </dl> <p class="First"> <span class="Bold">The most common side effects of budesonide extended-release tablets include:</span> </p> </td> </tr> <tr> <td class="Lrule" valign="top"> <dl> <dt>•</dt> <dd>headache</dd> <dt>•</dt> <dd>nausea</dd> <dt>•</dt> <dd>decreased blood</dd> <dt>•</dt> <dd>cortisol levels</dd> <dt>•</dt> <dd>stomach-area pain</dd> <dt>•</dt> <dd>tiredness</dd> </dl> </td><td class="Rrule" valign="top"> <dl> <dt>•</dt> <dd>stomach or intestinal gas</dd> <dt>•</dt> <dd>bloating</dd> <dt>•</dt> <dd>acne</dd> <dt>•</dt> <dd>urinary tract infection</dd> <dt>•</dt> <dd>joint pain</dd> <dt>•</dt> <dd>constipation</dd> </dl> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First">Tell your healthcare provider if you have any side effect that bothers you or that does not go away. </p> <p>These are not all the possible side effects of budesonide extended-release tablets. For more information, ask your healthcare provider or pharmacist. </p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">How should I store budesonide extended-release tablets? </span> </p> <dl> <dt>•</dt> <dd>Store budesonide extended-release tablets at room temperature, between 20° to 25°C (68° to 77°F). </dd> <dt>•</dt> <dd>Keep the bottle tightly closed to protect budesonide extended-release tablets from light and moisture. </dd> </dl> <p> <span class="Bold">Keep budesonide extended-release tablets and all medicines out of the reach of children. </span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of budesonide extended-release tablets.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide extended-release tablets for a condition for which they were not prescribed. Do not give budesonide extended-release tablets to other people, even if they have the same symptoms you have. They may harm them. </p> <p>You can ask your healthcare provider or pharmacist for information about budesonide extended-release tablets that is written for health professionals. </p> <p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" colspan="2" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in budesonide extended-release tablets? </span> </p> <p> <span class="Bold">Active ingredient:</span> budesonide </p> <p> <span class="Bold">Inactive ingredients:</span> colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and type B, microcrystalline cellulose, polyethylene glycol, polydextrose, talc, titanium dioxide, triacetin and triethyl citrate. </p> <p>In addition, the black imprinting ink contains black iron oxide, hypromellose and propylene glycol.</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" colspan="2" valign="top"> <p class="First">Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Budesonide Extended-Release Tablets</span>\n</p>\n<p>\n<span class=\"Bold\">(bue desʹ oh nide)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are budesonide extended-release tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Budesonide extended-release tablets are a prescription corticosteroid medicine used to help get active mild to moderate ulcerative colitis (UC) under control (induce remission). </dd>\n<dt>•</dt>\n<dd>It is not known if budesonide extended-release tablets are safe and effective in children. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not take budesonide extended-release tablets? </span>\n</p>\n<p>Do not take budesonide extended-release tablets if: </p>\n<dl>\n<dt>•</dt>\n<dd>you are allergic to budesonide or any of the ingredients in budesonide extended-release tablets. See the end of this leaflet for a complete list of ingredients in budesonide extended-release tablets. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before taking budesonide extended-release tablets? </span>\n</p>\n<p>\n<span class=\"Bold\">Before you take budesonide extended-release tablets tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems. </dd>\n<dt>•</dt>\n<dd>are planning to have surgery.</dd>\n<dt>•</dt>\n<dd>have chickenpox or measles or have recently been near anyone with chickenpox or measles.</dd>\n<dt>•</dt>\n<dd>have an infection, including fungal and threadworm (<span class=\"Italics\">Strongyloides</span>) infections.</dd>\n<dt>•</dt>\n<dd>have or had a family history of diabetes, cataracts or glaucoma.</dd>\n<dt>•</dt>\n<dd>have or had tuberculosis.</dd>\n<dt>•</dt>\n<dd>have high blood pressure (hypertension).</dd>\n<dt>•</dt>\n<dd>have decreased bone mineral density (osteoporosis).</dd>\n<dt>•</dt>\n<dd>have stomach ulcers.</dd>\n<dt>•</dt>\n<dd>have malaria of the brain (cerebral malaria).</dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. Budesonide extended-release tablets may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will take budesonide extended-release tablets or breastfeed. You should not do both. </dd>\n</dl>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take, </span>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide extended-release tablets and other medicines may affect each other causing side effects.</p>\n<p>Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I take budesonide extended-release tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Take budesonide extended-release tablets exactly as your healthcare provider tells you to take them. </dd>\n<dt>•</dt>\n<dd>Take budesonide extended-release tablets 1 time each day in the morning with or without food. </dd>\n<dt>•</dt>\n<dd>Take budesonide extended-release tablets whole with water. Do not chew, crush, or break budesonide extended-release tablets before swallowing. </dd>\n<dt>•</dt>\n<dd>If you take too many budesonide extended-release tablets, call your healthcare provider right away or go to the nearest hospital emergency room. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while taking budesonide extended-release tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Do not eat grapefruit or drink grapefruit juice while taking budesonide extended-release tablets. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide in your blood. </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of budesonide extended-release tablets? </span>\n</p>\n<p>Budesonide extended-release tablets may cause serious side effects, including:</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Effects of having too much corticosteroid medicine in your blood (hypercorticism). </span>Long-time use of budesonide extended-release tablets can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: <dl>\n<dt>o</dt>\n<dd>acne </dd>\n<dt>o</dt>\n<dd>bruise easily </dd>\n<dt>o</dt>\n<dd>rounding of your face (moon face) </dd>\n<dt>o</dt>\n<dd>ankle swelling </dd>\n<dt>o</dt>\n<dd>thicker or more hair on your body and face </dd>\n<dt>o</dt>\n<dd>a fatty pad or hump between your shoulders (buffalo hump) </dd>\n<dt>o</dt>\n<dd>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Adrenal suppression. </span>When budesonide extended-release tablets are taken for a long period of time (chronic use), the adrenal glands do not make enough steroid hormones (adrenal suppression). <br/>Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide extended-release tablets including: </dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>tiredness</dd>\n<dt>o</dt>\n<dd>weakness</dd>\n<dt>o</dt>\n<dd>nausea</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>vomiting</dd>\n<dt>o</dt>\n<dd>low blood pressure</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Decreased ability of your body to fight infections (immunosuppression) and increased risk of infection.<br/>\n</span>Corticosteroid medicines, including budesonide extended-release tablets, lower the ability of your immune system to fight infections and increase the risk of infections caused by viruses, bacteria, fungi, protozoan, or certain parasites. Corticosteroid medicines, including budesonide extended-release tablets, can also:<dl>\n<dt>o</dt>\n<dd>make current infections worse</dd>\n<dt>o</dt>\n<dd>increase the risk of infections spreading (disseminated)</dd>\n<dt>o</dt>\n<dd>increase the risk of making infections active again or making infections worse that have not been active (latent)</dd>\n<dt>o</dt>\n<dd>hide (mask) some signs of infection</dd>\n</dl>\n</dd>\n</dl>\n<p class=\"First\">These infections can be mild but can be severe and lead to death. Your healthcare provider should check you closely for signs and symptoms of an infection while taking budesonide extended-release tablets. Tell you healthcare provider right away about any signs or symptoms of a new or worsening infection while taking budesonide extended-release tablets, including flu-like symptoms such as:</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>fever</dd>\n<dt>o</dt>\n<dd>chills</dd>\n<dt>o</dt>\n<dd>stomach area (abdominal)<br/>pain</dd>\n<dt>o</dt>\n<dd>aches</dd>\n<dt>o</dt>\n<dd>diarrhea</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>o</dt>\n<dd>cough</dd>\n<dt>o</dt>\n<dd>pain</dd>\n<dt>o</dt>\n<dd>feeling tired</dd>\n<dt>o</dt>\n<dd>nausea and vomiting</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<dl>\n<dt> </dt>\n<dd>\n<dl>\n<dt>o</dt>\n<dd>Tuberculosis: If you have inactive (latent) tuberculosis, your tuberculosis may become active again while taking budesonide extended-release tablets. Your healthcare provider should check you closely for signs and symptoms of tuberculosis while taking budesonide extended-release tablets. </dd>\n<dt>o</dt>\n<dd>Chickenpox and measles: People taking corticosteroid medicines, including budesonide extended-release tablets, who have not had chickenpox or measles, should avoid contact with people who have these diseases. Tell your healthcare provider right away if you come in contact with anyone who has chickenpox or measles. </dd>\n<dt>o</dt>\n<dd>Hepatitis B virus (HBV) reactivation: If you are a carrier of HBV, the virus can become an active infection again while taking budesonide extended-release tablets. Your healthcare provider will test you for HBV before you start taking budesonide extended-release tablets. </dd>\n<dt>o</dt>\n<dd>Amebiasis: Inactive (latent) amebiasis may become an active infection while taking budesonide extended-release tablets. Your healthcare provider should check you for amebiasis before you start taking budesonide extended-release tablets in people who have spent time in the tropics or have unexplained diarrhea. </dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>Kaposi’s sarcoma. Kaposi’s sarcoma has happened in people who received corticosteroid therapy, most often for treatment of long-lasting (chronic) conditions.</dd>\n<dt>•</dt>\n<dd>Worsening of allergies. If you take certain other corticosteroid medicines to treat allergies, switching to budesonide extended-release tablets may cause your allergies to come back. These allergies may include eczema (a skin disease) or rhinitis (inflammation inside your nose). Tell your healthcare provider if any of your allergies become worse while taking budesonide extended-release tablets.</dd>\n</dl>\n<p class=\"First\">\n<span class=\"Bold\">The most common side effects of budesonide extended-release tablets include:</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Lrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>headache</dd>\n<dt>•</dt>\n<dd>nausea</dd>\n<dt>•</dt>\n<dd>decreased blood</dd>\n<dt>•</dt>\n<dd>cortisol levels</dd>\n<dt>•</dt>\n<dd>stomach-area pain</dd>\n<dt>•</dt>\n<dd>tiredness</dd>\n</dl>\n</td><td class=\"Rrule\" valign=\"top\">\n<dl>\n<dt>•</dt>\n<dd>stomach or intestinal gas</dd>\n<dt>•</dt>\n<dd>bloating</dd>\n<dt>•</dt>\n<dd>acne</dd>\n<dt>•</dt>\n<dd>urinary tract infection</dd>\n<dt>•</dt>\n<dd>joint pain</dd>\n<dt>•</dt>\n<dd>constipation</dd>\n</dl>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">Tell your healthcare provider if you have any side effect that bothers you or that does not go away. </p>\n<p>These are not all the possible side effects of budesonide extended-release tablets. For more information, ask your healthcare provider or pharmacist. </p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store budesonide extended-release tablets? </span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store budesonide extended-release tablets at room temperature, between 20° to 25°C (68° to 77°F). </dd>\n<dt>•</dt>\n<dd>Keep the bottle tightly closed to protect budesonide extended-release tablets from light and moisture. </dd>\n</dl>\n<p>\n<span class=\"Bold\">Keep budesonide extended-release tablets and all medicines out of the reach of children. </span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of budesonide extended-release tablets.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide extended-release tablets for a condition for which they were not prescribed. Do not give budesonide extended-release tablets to other people, even if they have the same symptoms you have. They may harm them. </p>\n<p>You can ask your healthcare provider or pharmacist for information about budesonide extended-release tablets that is written for health professionals. </p>\n<p>For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). </p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in budesonide extended-release tablets? </span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> budesonide </p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and type B, microcrystalline cellulose, polyethylene glycol, polydextrose, talc, titanium dioxide, triacetin and triethyl citrate. </p>\n<p>In addition, the black imprinting ink contains black iron oxide, hypromellose and propylene glycol.</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" colspan=\"2\" valign=\"top\">\n<p class=\"First\">Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration. " }

Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc. \nMorgantown, WV 26505 U.S.A." }

Manufactured by: ALPHAPHARM PTY LTD 15 Garnet StreetCarole Park QLD 4300Australia

{ "type": "p", "children": [], "text": "Manufactured by: \nALPHAPHARM PTY LTD\n15 Garnet StreetCarole Park QLD 4300Australia" }

Revised: 11/2024ALP:BUDEERT:R3(3491/2)

{ "type": "p", "children": [], "text": "Revised: 11/2024ALP:BUDEERT:R3(3491/2)" }

NDC 0378-4500-93

{ "type": "p", "children": [], "text": "\nNDC 0378-4500-93\n" }

BudesonideExtended-ReleaseTablets

{ "type": "p", "children": [], "text": "\nBudesonideExtended-ReleaseTablets\n" }

9 mg

{ "type": "p", "children": [], "text": "\n9 mg\n" }

Swallow tablet whole, do not chew, crush, or break.

{ "type": "p", "children": [], "text": "Swallow tablet whole, do not chew, crush, or break." }

Rx only30 Tablets

{ "type": "p", "children": [], "text": "\nRx only30 Tablets\n" }

Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure.

{ "type": "p", "children": [], "text": "Dispense in a tight, light-resistantcontainer as defined in the USPusing a child-resistant closure." }

Keep container tightly closed. Keep this and all medicationout of the reach of children.

{ "type": "p", "children": [], "text": "Keep container tightly closed.\nKeep this and all medicationout of the reach of children.\n" }

Store at 20° to 25°C (68° to 77°F).[See USP Controlled Room Temperature.]

{ "type": "p", "children": [], "text": "\nStore at 20° to 25°C (68° to 77°F).[See USP Controlled Room Temperature.]\n" }

Protect from light and moisture.

{ "type": "p", "children": [], "text": "\nProtect from light and moisture.\n" }

Usual Dosage: One tablet daily.See accompanying prescribinginformation.

{ "type": "p", "children": [], "text": "\nUsual Dosage: One tablet daily.See accompanying prescribinginformation." }

Budesonide extended-release tabletsshould be swallowed whole and notchewed, crushed, or broken.

{ "type": "p", "children": [], "text": "Budesonide extended-release tabletsshould be swallowed whole and notchewed, crushed, or broken." }

Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Made in Australia

{ "type": "p", "children": [], "text": "Manufactured for:\nMylan Pharmaceuticals Inc.,\nMorgantown, WV 26505 U.S.A.Made in Australia " }

Each extended-release tablet contains:Budesonide, USP    9 mg

{ "type": "p", "children": [], "text": "Each extended-release tablet contains:Budesonide, USP    9 mg" }

RALP4500H

{ "type": "p", "children": [], "text": "\nRALP4500H\n" }

Budesonide rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

{ "type": "p", "children": [], "text": "Budesonide rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge." }

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Advise patients:

Budesonide rectal foam is formulated as an emulsion which is filled into an aluminum canister with an aerosol propellant. It is available in 1 strength: 2 mg budesonide per metered dose.

{ "type": "p", "children": [], "text": "Budesonide rectal foam is formulated as an emulsion which is filled into an aluminum canister with an aerosol propellant. It is available in 1 strength: 2 mg budesonide per metered dose." }

Budesonide rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of budesonide rectal foam. Reactions have included anaphylaxis [see Adverse Reactions (6.2)].

{ "type": "p", "children": [], "text": "Budesonide rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of budesonide rectal foam. Reactions have included anaphylaxis [see Adverse Reactions (6.2)]." }

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since budesonide rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed [see Clinical Pharmacology (12.2)].

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use in Specific Populations (8.6)].

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as budesonide rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with budesonide rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

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 patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid 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 prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

The contents of budesonide rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of budesonide rectal foam before initiation of bowel preparation for colonoscopy and consult their healthcare provider before resuming therapy.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to budesonide rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

Budesonide rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received budesonide rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks [see Clinical Studies (14)].

The most common adverse reactions (≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of budesonide rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo-Controlled Trials* (Studies 1 and 2)

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule Toprule" valign="bottom"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Budesonide Rectal Foam</span> </p> <p> <span class="Bold">2 mg/25 mL</span> </p> <p> <span class="Bold">N=268</span> </p> <p> <span class="Bold">n (%)</span> </p> </td><td align="center" class="Botrule Toprule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=278</span> </p> <p> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Decreased blood cortisol <span class="Sup">#</span> </p> </td><td align="center" valign="top"> <p class="First">46 (17)</p> </td><td align="center" valign="top"> <p class="First">6 (2)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Adrenal insufficiency<span class="Sup">†</span> </p> </td><td align="center" valign="top"> <p class="First">10 (4)</p> </td><td align="center" valign="top"> <p class="First">2 (1)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Nausea</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">6 (2)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">2 (1)</p> </td> </tr> </tbody> </table></div>

*Experienced by ≥ 2% of the budesonide rectal foam or Placebo group and at higher frequency in the budesonide rectal foam group.

#Decreased blood cortisol was defined as a morning cortisol level of <5 mcg/dL.

†Adrenal insufficiency was defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH.

Of the 46 budesonide rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of <5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of <18 mcg/dL at 30 minutes post-challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

<div class="scrollingtable"><table width="100%"> <col width="33%"/> <col width="33%"/> <col width="33%"/> <tbody class="Headless"> <tr class="First"> <td class="Botrule" valign="bottom"> <p class="First"> <span class="Bold">Adverse Reaction</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Budesonide Rectal Foam</span> </p> <p> <span class="Bold">2 mg/25 mL</span> </p> <p> <span class="Bold">N=268</span> </p> <p> <span class="Bold">n (%)</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=278</span> </p> <p> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Overall</p> </td><td align="center" valign="top"> <p class="First">60 (22)</p> </td><td align="center" valign="top"> <p class="First">10 (4)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Blood cortisol decreased</p> </td><td align="center" valign="top"> <p class="First">46 (17)<span class="Sup">*</span> </p> </td><td align="center" valign="top"> <p class="First">6 (2)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Adrenal insufficiency</p> </td><td align="center" valign="top"> <p class="First">10 (4)</p> </td><td align="center" valign="top"> <p class="First">2 (1)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Insomnia</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Sleep disorder</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Acne</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" valign="top"> <p class="First">0</p> </td> </tr> <tr> <td valign="top"> <p class="First">Depression</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" valign="top"> <p class="First">1 (0.4)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Hyperglycemia</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">1 (0.4)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">0</p> </td> </tr> </tbody> </table></div>

*Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice daily treatment) in the budesonide rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between budesonide rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see Clinical Pharmacology (12.2).

In addition to adverse reactions reported from clinical trials for budesonide rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune system disorders: anaphylactic reactions

Nervous system disorders: dizziness, benign intracranial hypertension

Psychiatric disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculopapular rash, allergic dermatitis

The active ingredient of budesonide rectal foam, budesonide, is metabolized by CYP3A4. Inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, cyclosporine and grapefruit juice) can increase systemic budesonide concentrations. Avoid concomitant use of CYP3A4 inhibitors with budesonide rectal foam [see Clinical Pharmacology (12.3)].

Risk Summary

Limited published studies report on the use of budesonide in pregnant women; however, the data are insufficient to inform a drug-associated risk for major birth defects and miscarriage. There are clinical considerations (see Clinical Considerations). In animal reproduction studies with pregnant rats and rabbits, subcutaneous administration of budesonide during organogenesis at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, resulted in increased fetal loss, decreased pup weights, and skeletal abnormalities. Maternal toxicity was observed in both rats and rabbits at these dose levels (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is of 2% to 4%, and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Infants should be carefully observed for signs of hypoadrenalism, such as poor feeding, irritability, weakness, and vomiting, and managed accordingly [see Warnings and Precautions (5.1)].

Data

Animal Data

Budesonide was teratogenic and embryolethal in rabbits and rats.

In an embryo-fetal development study in pregnant rats dosed subcutaneously with budesonide during the period of organogenesis from gestation days 6-15 there were effects on fetal development and survival at subcutaneous doses up to approximately 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose on a body surface area basis). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation days 6-18, there was an increase in maternal abortion, and effects on fetal development and reduction in litter weights at subcutaneous doses up to approximately 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis). Maternal toxicity, including reduction in body weight gain, was observed at subcutaneous doses of 5 mcg/kg in rabbits (approximately 0.02 times the recommended human intrarectal dose on a body surface area basis) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day on a body surface area basis).

In a pre-and post-natal development study, rats dosed subcutaneously with budesonide during the period of Day 15 post coitum to Day 21 postpartum, budesonide had no effects on delivery but did have an effect on growth and development of offspring. In addition, offspring survival was reduced, and surviving offspring had decreased mean body weights at birth and during lactation at exposures 0.05 times the MRHD (on a mg/m2 basis at maternal subcutaneous doses of 20 mcg/kg/day and higher). These findings occurred in the presence of maternal toxicity.

Risk Summary

Lactation studies have not been conducted with budesonide rectal foam or other rectally administered budesonide products and no information is available on the effects of budesonide on the breastfed infant or the effects of the drug on milk production. One published study reports that budesonide is present in human milk following maternal inhalation of budesonide (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for budesonide rectal foam and any potential adverse effects on the breastfed child from budesonide rectal foam or from the underlying maternal condition.

Data

One published study reports that budesonide is present in human milk following maternal inhalation of budesonide and the milk/plasma ratio ranged between 0.4 and 0.5. Budesonide plasma concentrations were not detected, and no adverse events were noted in the breastfed infants following maternal use of inhaled budesonide. The systemic exposure (AUC0-12) following administration of 400 mcg twice a day of inhaled budesonide ranged from 1.27 to 2.26 ng*hr/mL. The estimated budesonide AUC0-12 following rectal administration of 2 mg twice a day budesonide was 4.31 ng*hr/mL [see Clinical Pharmacology (12.3)]. Budesonide exposure to the nursing child may be higher with maternal rectal administration of budesonide than with maternal inhaled administration of budesonide.

The safety and effectiveness of budesonide rectal foam has not been established in pediatric patients.

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Clinical studies with budesonide rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and 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.

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of budesonide rectal foam should be considered in these patients if signs of hypercorticism are observed [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Acute overdosage with budesonide rectal foam is unlikely. However, budesonide rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.1)].

{ "type": "p", "children": [], "text": "Acute overdosage with budesonide rectal foam is unlikely. However, budesonide rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.1)]." }

Budesonide rectal foam contains budesonide, a non-halogenated synthetic glucocorticoid, as the active ingredient. It is a mixture of the 2 epimers (22R and 22S) differing in the position of an acetal chain. Both epimers are active glucocorticoids applied in a mixture of approximately 1:1.

{ "type": "p", "children": [], "text": "Budesonide rectal foam contains budesonide, a non-halogenated synthetic glucocorticoid, as the active ingredient. It is a mixture of the 2 epimers (22R and 22S) differing in the position of an acetal chain. Both epimers are active glucocorticoids applied in a mixture of approximately 1:1." }

Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5.

{ "type": "p", "children": [], "text": "Budesonide is designated chemically as (RS)-11β, 16α, 17,21 tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. The empirical formula of budesonide is C25H34O6 and its molecular weight is 430.5." }

Its structural formula is:

{ "type": "p", "children": [], "text": "Its structural formula is:" }

Budesonide rectal foam contains 2 mg budesonide per metered dose.

{ "type": "p", "children": [], "text": "Budesonide rectal foam contains 2 mg budesonide per metered dose." }

Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water.

{ "type": "p", "children": [], "text": "Inactive ingredients: cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water." }

Propellant: n-butane, isobutane, and propane.

{ "type": "p", "children": [], "text": "Propellant: n-butane, isobutane, and propane." }

Budesonide has glucocorticosteroid (GCS) activity.

Treatment with glucocorticosteroids, including budesonide rectal foam, is associated with a suppression of endogenous cortisol concentrations and an impairment of the hypothalamic-pituitary-adrenal (HPA) axis function. These effects were measured by determination of plasma cortisol concentrations and responses to adrenocorticotropin challenge (i.e., ACTH stimulation test) in 2 placebo-controlled, 6-week trials in patients with active disease [see Clinical Studies (14)]. These trials enrolled subjects with post-ACTH stimulation cortisol levels of >18 mcg/dL at baseline. Subjects received budesonide rectal foam 2 mg or a placebo twice daily for 2 weeks followed by once daily for 4 weeks. Normal morning serum cortisol levels >5 mcg/dL were maintained in 85% and 84% of budesonide rectal foam treated subjects during Weeks 1 and 2 (twice daily treatment) and 93% and 94% during Weeks 4 and 6 (once daily treatment), respectively (see Table 3).

At baseline (predose), 84% of subjects in the budesonide rectal foam group had a normal response to the ACTH challenge and at Week 6, 63% of subjects had a normal response to the ACTH challenge; in the placebo group, these values were 86% and 76%, respectively (see Table 3). ACTH stimulation test was not performed routinely during the twice daily treatment period (Weeks 1 and 2).

Table 3: Proportion of Subjects with Normal Endogenous Cortisol Levels (>5 mcg/dL) During the Study and Proportion of Subjects with Normal Response to ACTH Challenge

<div class="scrollingtable"><table width="100%"> <col width="38%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <tbody class="Headless"> <tr class="First"> <td class="Toprule" valign="bottom"> <p class="First"> <span class="Bold">Cortisol Parameter</span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Budesonide Rectal Foam</span> </p> <p> <span class="Bold">2 mg/25 mL</span> </p> <p> <span class="Bold">N=268</span> </p> <p> <span class="Bold">n (%)</span> </p> </td><td align="center" class="Toprule" colspan="2" valign="top"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=278</span> </p> <p> <span class="Bold">n (%)</span> </p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Total cortisol </span>&gt;<span class="Italics">5 mcg/dL</span></span> </p> <p> <span class="Bold"><span class="Italics">(lower limit of normal range)</span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Baseline</p> </td><td align="center" valign="top"> <p class="First">259/268</p> </td><td align="center" valign="top"> <p class="First">(96.6)</p> </td><td align="center" valign="top"> <p class="First">275/278</p> </td><td align="center" valign="top"> <p class="First">(98.9)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Week 1</p> </td><td align="center" valign="top"> <p class="First">224/263</p> </td><td align="center" valign="top"> <p class="First">(85.2)</p> </td><td align="center" valign="top"> <p class="First">264/269</p> </td><td align="center" valign="top"> <p class="First">(98.1)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Week 2</p> </td><td align="center" valign="top"> <p class="First">216/257</p> </td><td align="center" valign="top"> <p class="First">(84.0)</p> </td><td align="center" valign="top"> <p class="First">263/266</p> </td><td align="center" valign="top"> <p class="First">(98.9)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Week 4</p> </td><td align="center" valign="top"> <p class="First">218/235</p> </td><td align="center" valign="top"> <p class="First">(92.8)</p> </td><td align="center" valign="top"> <p class="First">243/249</p> </td><td align="center" valign="top"> <p class="First">(97.6)</p> </td> </tr> <tr> <td valign="top"> <p class="First">Week 6</p> </td><td align="center" valign="top"> <p class="First">211/224</p> </td><td align="center" valign="top"> <p class="First">(94.2)</p> </td><td align="center" valign="top"> <p class="First">234/241</p> </td><td align="center" valign="top"> <p class="First">(97.1)</p> </td> </tr> <tr> <td colspan="5" valign="top"> <p class="First"> <span class="Bold"><span class="Italics">Normal response to ACTH challenge<span class="Sup">a</span></span></span> </p> </td> </tr> <tr> <td valign="top"> <p class="First">Baseline</p> </td><td align="center" valign="top"> <p class="First">222/266</p> </td><td align="center" valign="top"> <p class="First">(83.5)</p> </td><td align="center" valign="top"> <p class="First">238/278</p> </td><td align="center" valign="top"> <p class="First">(85.6)</p> </td> </tr> <tr class="Last"> <td class="Botrule" valign="top"> <p class="First">Week 6<span class="Sup">b</span> </p> </td><td align="center" class="Botrule" valign="top"> <p class="First">148/236</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(62.7)</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">180/237</p> </td><td align="center" class="Botrule" valign="top"> <p class="First">(75.9)</p> </td> </tr> </tbody> </table></div>

aThe normal response to ACTH challenge included 3 criteria, as defined in the cosyntropin label: 1) morning cortisol level >5 mcg/dL; 2) increase in cortisol level by ≥7 mcg/dL above the morning (pre-challenge) level following ACTH challenge; and cortisol level of >18 mcg/dL following ACTH challenge.

bDenominator includes 20 subjects in the budesonide rectal foam arm and 2 subjects in the placebo arm who discontinued prior to Week 6 due to adverse events related to low cortisol or abnormal response to ACTH challenge.

Absorption

Distal Ulcerative Colitis Patients

Based on population pharmacokinetic analysis from sparse PK samples from phase 3 studies, the estimated AUC0-12 following administration of budesonide rectal foam 2 mg twice a day was 4.31 ng*hr/mL with a CV of 64% in the target patient population.

Distribution

The volume of distribution (VSS) of budesonide varies between 2.2 and 3.9 L/kg in healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in the concentration range of 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma partition ratio at clinically relevant concentrations is approximately 0.8.

Elimination

Metabolism

Following absorption, budesonide is subject to first-pass metabolism. In vitro experiments in human liver microsomes demonstrate that budesonide is rapidly and extensively biotransformed, mainly by CYP3A4, to its 2 major metabolites, 6β-hydroxy budesonide and 16α-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound.

In vivo investigations with intravenous doses in healthy subjects demonstrate that budesonide has a plasma clearance of 0.9-1.8 L/min. These plasma clearance values approach the estimated liver blood flow, suggesting that budesonide is a high hepatic clearance drug.

Excretion

Budesonide is excreted in urine and feces in the form of metabolites. After oral as well as intravenous administration of micronized [3H]-budesonide, approximately 60% of the recovered radioactivity is found in urine. The major metabolites, including 6β-hydroxybudesonide and 16α-hydroxyprednisolone, are mainly renally excreted, intact or in conjugated forms. No unchanged budesonide is detected in urine.

Specific Populations

Patients with Renal Impairment

The pharmacokinetics of budesonide in patients with renal impairment has not been studied. Intact budesonide is not renally excreted, but metabolites are to a large extent, and might therefore reach higher levels in patients with impaired renal function. However, these metabolites have negligible corticosteroid activity as compared with budesonide.

Patients with Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of budesonide rectal foam has not been studied. In a study in patients with mild to moderate hepatic impairment (Child-Pugh Class A and Child-Pugh Class B) dosed with budesonide 4 mg oral capsules, systemic exposure was similar between patients with mild hepatic impairment (Child-Pugh Class A; n=4) and healthy subjects (n=8), and 3.5-fold higher in patients with moderate hepatic impairment (Child-Pugh Class B; n=4) than in healthy subjects. For the intravenous dose, no significant differences in CL or VSS are observed. Patients with severe liver dysfunction (Child-Pugh Class C) were not studied [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma concentrations of budesonide. Co-administration of ketoconazole (inhibitor of CYP3A4) results in an 8-fold increase in AUC of oral budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor of gut mucosal CYP3A, approximately doubles the systemic exposure of oral budesonide. Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma concentrations. The effect of CYP3A4 inhibitors and inducers on the pharmacokinetics of budesonide rectal foam have not been studied [see Dosage and Administration (2) and Drug Interactions (7)].

Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do not affect the pharmacokinetics of oral budesonide. Budesonide does not affect the plasma concentrations of oral contraceptives (i.e., ethinyl estradiol).

In vitro interaction studies performed with budesonide showed that budesonide did not inhibit human cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6, or CYP2E1 at concentrations ranging from 0.11 to 1130 ng/mL. Isoenzyme CYP3A4 was inhibited at the highest concentration tested but the IC50 was >1130 ng/mL. Budesonide rectal foam is not expected to inhibit these enzymes in clinical use. No significant induction of CYP1A2, CYP2B6, CYP2C9 or CYP3A4/5 expression was observed in human hepatocytes in vitro at budesonide concentrations up to 9000 nM (3.88 mcg/mL).

In an in vitro study, budesonide was not a substrate of human transporters OATP1B3 and may be a weak substrate of OATP1B1. Budesonide at concentrations up to 300 nM (129 ng/mL) did not inhibit OATP1B1 or OATP1B3.

Budesonide was not a substrate of BCRP and was a weak substrate of P-glycoprotein. Budesonide was a weak inhibitor of P-glycoprotein (IC50 9.78 μM or 4.21 mcg/mL) and BCRP (IC50 43.1 μM or 18.6 mcg/mL). Budesonide rectal foam is not expected to inhibit these transporters in clinical use.

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-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 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

The safety and efficacy of budesonide rectal foam were evaluated in 2 replicate, randomized, double-blind, placebo-controlled, multi-center trials (Studies 1 and 2).

{ "type": "p", "children": [], "text": "The safety and efficacy of budesonide rectal foam were evaluated in 2 replicate, randomized, double-blind, placebo-controlled, multi-center trials (Studies 1 and 2)." }

Participants in the trials were adult patients with active mild-to-moderate distal ulcerative colitis with disease extending at least 5 cm but no further than 40 cm from the anal verge (confirmed by endoscopy). To be eligible, patients had to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3, and an endoscopy subscore of 2 or 3. The MMDAI score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration.

{ "type": "p", "children": [], "text": "Participants in the trials were adult patients with active mild-to-moderate distal ulcerative colitis with disease extending at least 5 cm but no further than 40 cm from the anal verge (confirmed by endoscopy). To be eligible, patients had to have a Modified Mayo Disease Activity Index (MMDAI) score between 5 and 10, inclusive, a rectal bleeding subscore of 2 or 3, and an endoscopy subscore of 2 or 3. The MMDAI score ranges from 0 to 12 and has 4 subscales that are each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of 2 is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration." }

Oral and rectal corticosteroids, and rectal 5-aminosalicylic acid (5-ASA) products were prohibited during the course of the trials but were allowed as rescue therapy. Oral 5-ASA products were allowed at doses ≤ 4.8 grams/day.

{ "type": "p", "children": [], "text": "Oral and rectal corticosteroids, and rectal 5-aminosalicylic acid (5-ASA) products were prohibited during the course of the trials but were allowed as rescue therapy. Oral 5-ASA products were allowed at doses ≤ 4.8 grams/day." }

In total, 546 subjects were randomized in these trials: 267 subjects to budesonide rectal foam and 279 subjects to placebo. In each trial (Study 1 and Study 2), patients received budesonide rectal foam 2 mg or placebo twice daily for 2 weeks followed by once daily for 4 weeks.

{ "type": "p", "children": [], "text": "In total, 546 subjects were randomized in these trials: 267 subjects to budesonide rectal foam and 279 subjects to placebo. In each trial (Study 1 and Study 2), patients received budesonide rectal foam 2 mg or placebo twice daily for 2 weeks followed by once daily for 4 weeks." }

The median age was 41 years and 42 years, 5% and 8% were ≥ 65 years of age, and 43% and 45% were male, in Studies 1 and 2, respectively. In each of these trials, 90% were Caucasian, 7-8% were African American, and 3% were Asian or Other.

{ "type": "p", "children": [], "text": "The median age was 41 years and 42 years, 5% and 8% were ≥ 65 years of age, and 43% and 45% were male, in Studies 1 and 2, respectively. In each of these trials, 90% were Caucasian, 7-8% were African American, and 3% were Asian or Other." }

The majority of patients had a baseline diagnosis of proctosigmoiditis (69% and 74%) in Studies 1 and 2, respectively. The remaining patients had a baseline diagnosis of proctitis. Concomitant oral 5-ASA use at baseline was 59% and 51% in Studies 1 and 2, respectively.

{ "type": "p", "children": [], "text": "The majority of patients had a baseline diagnosis of proctosigmoiditis (69% and 74%) in Studies 1 and 2, respectively. The remaining patients had a baseline diagnosis of proctitis. Concomitant oral 5-ASA use at baseline was 59% and 51% in Studies 1 and 2, respectively." }

Baseline MMDAI total score was 7.8 and 7.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 7.9 and 8.0 in the budesonide rectal foam group and placebo group, respectively, of Study 2. The mean stool frequency subscore at baseline was 1.8 and 1.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 1.7 and 1.8 in the budesonide rectal foam group and placebo group, respectively, of Study 2.

{ "type": "p", "children": [], "text": "Baseline MMDAI total score was 7.8 and 7.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 7.9 and 8.0 in the budesonide rectal foam group and placebo group, respectively, of Study 2. The mean stool frequency subscore at baseline was 1.8 and 1.9 in the budesonide rectal foam group and placebo group, respectively, of Study 1; and 1.7 and 1.8 in the budesonide rectal foam group and placebo group, respectively, of Study 2." }

In each trial (Study 1 and Study 2), the primary endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. (An endoscopy subscore of zero is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.)

{ "type": "p", "children": [], "text": "In each trial (Study 1 and Study 2), the primary endpoint was the proportion of subjects who were in remission after 6 weeks of treatment. Remission was defined as a decrease or no change in the stool frequency subscore from baseline, a rectal bleeding subscore of 0, and an endoscopy score of 0 or 1. (An endoscopy subscore of zero is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern.)" }

In each trial (Study 1 and Study 2), a higher proportion of patients in the budesonide rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 (Table 4).

{ "type": "p", "children": [], "text": "In each trial (Study 1 and Study 2), a higher proportion of patients in the budesonide rectal foam group than in the placebo group were in remission at Week 6 and had a rectal bleeding subscore of 0 at Week 6 (Table 4)." }

Table 4: Efficacy Results: Studies 1 and 2

{ "type": "p", "children": [], "text": "\nTable 4: Efficacy Results: Studies 1 and 2\n" }

<div class="scrollingtable"><table width="100%"> <col width="29%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <col width="18%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" colspan="5" valign="top"> <p class="First"> <span class="Bold">Study 1</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First"> <span class="Bold">Efficacy Endpoint</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Budesonide</span> </p> <p> <span class="Bold">Rectal Foam</span> </p> <p> <span class="Bold">N=133</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=132</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">p-value<span class="Sup">b</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Treatment</span> </p> <p> <span class="Bold">Difference</span> </p> <p> <span class="Bold">(95% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Remission at Week 6<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">38.3%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">25.8%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.032</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">12.6%</p> <p>(1.5%, 23.7%)</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Rectal Bleeding subscore</p> <p>= 0 at Week 6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">46.6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">28.0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">0.002</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">18.6%</p> <p>(7.2%, 30%)</p> </td> </tr> <tr> <td align="center" class="Botrule Lrule Rrule" colspan="5" valign="middle"> <p class="First"> <span class="Bold">Study 2</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"></td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Budesonide</span> </p> <p> <span class="Bold">Rectal Foam</span> </p> <p> <span class="Bold">N=134</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Placebo</span> </p> <p> <span class="Bold">N=147</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">p-value<span class="Sup">b</span></span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First"> <span class="Bold">Treatment</span> </p> <p> <span class="Bold">Difference</span> </p> <p> <span class="Bold">(95% CI)</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="middle"> <p class="First">Remission at Week 6<span class="Sup">a</span> </p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">44.0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">22.4%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;0.001</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21.6%</p> <p>(10.8%, 32.4%)</p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">Rectal Bleeding subscore</p> <p>= 0 at Week 6</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">50.0%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">28.6%</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">&lt;0.001</p> </td><td align="center" class="Botrule Lrule Rrule Toprule" valign="middle"> <p class="First">21.4%</p> <p>(10.3%, 32.6%)</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"29%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<col width=\"18%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" colspan=\"5\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Study 1</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Efficacy Endpoint</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Budesonide</span>\n</p>\n<p>\n<span class=\"Bold\">Rectal Foam</span>\n</p>\n<p>\n<span class=\"Bold\">N=133</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Placebo</span>\n</p>\n<p>\n<span class=\"Bold\">N=132</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">p-value<span class=\"Sup\">b</span></span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Treatment</span>\n</p>\n<p>\n<span class=\"Bold\">Difference</span>\n</p>\n<p>\n<span class=\"Bold\">(95% CI)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Remission at Week 6<span class=\"Sup\">a</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">38.3%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">25.8%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">0.032</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">12.6%</p>\n<p>(1.5%, 23.7%)</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Rectal Bleeding subscore</p>\n<p>= 0 at Week 6</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">46.6%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">28.0%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">0.002</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">18.6%</p>\n<p>(7.2%, 30%)</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" class=\"Botrule Lrule Rrule\" colspan=\"5\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Study 2</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\"></td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Budesonide</span>\n</p>\n<p>\n<span class=\"Bold\">Rectal Foam</span>\n</p>\n<p>\n<span class=\"Bold\">N=134</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Placebo</span>\n</p>\n<p>\n<span class=\"Bold\">N=147</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">p-value<span class=\"Sup\">b</span></span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">\n<span class=\"Bold\">Treatment</span>\n</p>\n<p>\n<span class=\"Bold\">Difference</span>\n</p>\n<p>\n<span class=\"Bold\">(95% CI)</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"middle\">\n<p class=\"First\">Remission at Week 6<span class=\"Sup\">a</span>\n</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">44.0%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">22.4%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">&lt;0.001</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">21.6%</p>\n<p>(10.8%, 32.4%)</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">Rectal Bleeding subscore</p>\n<p>= 0 at Week 6</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">50.0%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">28.6%</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">&lt;0.001</p>\n</td><td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"middle\">\n<p class=\"First\">21.4%</p>\n<p>(10.3%, 32.6%)</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

a Remission was defined as an endoscopy subscore of 0 or 1, a rectal bleeding subscore of 0, and a decrease or no change in stool frequency subscore from baseline.

{ "type": "p", "children": [], "text": "\na Remission was defined as an endoscopy subscore of 0 or 1, a rectal bleeding subscore of 0, and a decrease or no change in stool frequency subscore from baseline." }

b p-values obtained from the Cochran-Mantel-Haenszel (CMH) test.

{ "type": "p", "children": [], "text": "\nb p-values obtained from the Cochran-Mantel-Haenszel (CMH) test." }

CI: Confidence Interval

{ "type": "p", "children": [], "text": "CI: Confidence Interval" }

In Study 1, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 55.6% in the budesonide rectal foam group versus 43.2% in the placebo group. In Study 2, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 56.0% in the budesonide rectal foam group versus 36.7% in the placebo group (an endoscopy subscore of 0 is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern).

{ "type": "p", "children": [], "text": "In Study 1, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 55.6% in the budesonide rectal foam group versus 43.2% in the placebo group. In Study 2, the percentage of patients with endoscopy subscore of 0 or 1 at Week 6 was 56.0% in the budesonide rectal foam group versus 36.7% in the placebo group (an endoscopy subscore of 0 is defined by normal or inactive disease; an endoscopy subscore of 1 is defined by erythema and decreased vascular pattern)." }

In patients that met the primary endpoint of remission in Study 1, the mean (SD) decrease in stool frequency subscore was 1.2 (0.9) in the budesonide rectal foam group and 1.2 (0.8) in the placebo group. In patients that met the primary endpoint of remission in Study 2, the mean (SD) decrease in stool frequency subscore was 1.3 (0.8) in the budesonide rectal foam group and 1.1 (0.9) in the placebo group.

{ "type": "p", "children": [], "text": "In patients that met the primary endpoint of remission in Study 1, the mean (SD) decrease in stool frequency subscore was 1.2 (0.9) in the budesonide rectal foam group and 1.2 (0.8) in the placebo group. In patients that met the primary endpoint of remission in Study 2, the mean (SD) decrease in stool frequency subscore was 1.3 (0.8) in the budesonide rectal foam group and 1.1 (0.9) in the placebo group." }

Budesonide rectal foam is supplied as a kit containing 2 aerosol canisters with 28 PVC applicators coated with paraffin lubricant for administration of the foam (NDC 45802-627-86). Each canister (NDC 45802-627-01) is labeled with a net weight of 33.4 g and contains 14 metered doses.

{ "type": "p", "children": [], "text": "Budesonide rectal foam is supplied as a kit containing 2 aerosol canisters with 28 PVC applicators coated with paraffin lubricant for administration of the foam (NDC 45802-627-86). Each canister (NDC 45802-627-01) is labeled with a net weight of 33.4 g and contains 14 metered doses." }

Storage

{ "type": "p", "children": [], "text": "\nStorage\n" }

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

{ "type": "p", "children": [], "text": "Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]." }

Handling

{ "type": "p", "children": [], "text": "\nHandling\n" }

Budesonide rectal foam contains a flammable propellant. Do not have the canister burned after use and do not spray contents directly towards flames.

{ "type": "p", "children": [], "text": "Budesonide rectal foam contains a flammable propellant. Do not have the canister burned after use and do not spray contents directly towards flames." }

{ "type": "", "children": [], "text": "" }

DO NOT REFRIGERATE.

{ "type": "p", "children": [], "text": "DO NOT REFRIGERATE." }

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

{ "type": "p", "children": [], "text": "Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)." }

Administration

{ "type": "p", "children": [], "text": "\nAdministration\n" }

Advise patients:

{ "type": "p", "children": [], "text": "Advise patients:" }

{ "type": "", "children": [], "text": "" }

Hypercorticism and Adrenal Suppression

{ "type": "p", "children": [], "text": "\nHypercorticism and Adrenal Suppression\n" }

Advise patients that budesonide rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to budesonide rectal foam [see Warnings and Precautions (5.1), (5.2)]. Advise patients that replacement of systemic glucocorticosteroids with budesonide rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

{ "type": "p", "children": [], "text": "Advise patients that budesonide rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to budesonide rectal foam [see Warnings and Precautions (5.1), (5.2)]. Advise patients that replacement of systemic glucocorticosteroids with budesonide rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug." }

Increased Risk of Infection

{ "type": "p", "children": [], "text": "\nIncreased Risk of Infection\n" }

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection [see Warnings and Precautions (5.3)].

{ "type": "p", "children": [], "text": "Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection [see Warnings and Precautions (5.3)]." }

Pregnancy

{ "type": "p", "children": [], "text": "\nPregnancy\n" }

Advise female patients that budesonide rectal foam may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)].

{ "type": "p", "children": [], "text": "Advise female patients that budesonide rectal foam may cause fetal harm and to inform their healthcare provider with a known or suspected pregnancy [see Use in Specific Populations (8.1)]." }

Manufactured By Padagis, Yeruham 8050315, Israel

{ "type": "p", "children": [], "text": "Manufactured By Padagis, Yeruham 8050315, Israel" }

Distributed By Padagis, Allegan, MI 49010 www.padagis.com

{ "type": "p", "children": [], "text": "Distributed By Padagis, Allegan, MI 49010 www.padagis.com" }

Rev 06-22

{ "type": "p", "children": [], "text": "Rev 06-22" }

5Q200 RC J2

{ "type": "p", "children": [], "text": "5Q200 RC J2" }

Budesonide (bue-DES-oh-nide)

{ "type": "p", "children": [], "text": "\nBudesonide (bue-DES-oh-nide)\n" }

rectal foam

{ "type": "p", "children": [], "text": "\nrectal foam\n" }

Read the Patient Information and Instructions for Use that comes with budesonide rectal foam before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider if you have any questions.

{ "type": "p", "children": [], "text": "Read the Patient Information and Instructions for Use that comes with budesonide rectal foam before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider if you have any questions." }

Before using budesonide rectal foam, you should use the bathroom to empty your bowels.

{ "type": "p", "children": [], "text": "Before using budesonide rectal foam, you should use the bathroom to empty your bowels." }

You may use budesonide rectal foam while in a standing position, in a lying position, or in a sitting position (for example, while using the toilet).

{ "type": "p", "children": [], "text": "You may use budesonide rectal foam while in a standing position, in a lying position, or in a sitting position (for example, while using the toilet)." }

Applicators should be used only 1 time. You should use a new applicator for each dose.

{ "type": "p", "children": [], "text": "Applicators should be used only 1 time. You should use a new applicator for each dose." }

Each kit contains (See Figure A):

{ "type": "p", "children": [], "text": "Each kit contains (See Figure A):" }

{ "type": "", "children": [], "text": "" }

Preparing to use budesonide rectal foam

{ "type": "p", "children": [], "text": "\nPreparing to use budesonide rectal foam\n" }

<div class="scrollingtable"><table width="100%"> <col width="50%"/> <col width="50%"/> <tbody class="Headless"> <tr class="First Toprule"> <td align="center" valign="top"><a name="id-766929542"></a><img alt="figure-b" src="/dailymed/image.cfm?name=image-03.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure B</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 1: Twist Safety Tab to Remove</span> </p> <p>Before the first use, remove the safety tab from under the pump dome <span class="Bold">(See Figure B)</span>.</p> <p> <span class="Bold">The canister cannot be used if safety tab is not removed.</span> </p> </td> </tr> <tr> <td align="center" valign="top"><a name="id-263762878"></a><img alt="figure-c" src="/dailymed/image.cfm?name=image-04.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure C</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 2: Attach the Applicator</span> </p> <p>The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator.</p> <p>Push the applicator firmly onto the nozzle of the canister <span class="Bold">(See Figure C)</span>. Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly).</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id774825072"></a><img alt="figure-d" src="/dailymed/image.cfm?name=figure-d.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure D</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 3: Align Notch to Nozzle</span> </p> <p>To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle <span class="Bold">(See Figure D)</span>.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id1223788368"></a><img alt="figure-e" src="/dailymed/image.cfm?name=figure-e.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure E</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 4: Warm and Shake Canister</span> </p> <p>Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds <span class="Bold">(See Figure E)</span>.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id-1605415638"></a><img alt="figure-f" src="/dailymed/image.cfm?name=image-07.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure F</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 5: Turn the Canister Upside Down</span> </p> <p>Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down <span class="Bold">(See Figure F)</span>.</p> <p> <span class="Bold">The canister will only work properly when held with the pump dome pointing down.</span> </p> </td> </tr> <tr> <td align="center" valign="top"><a name="id164215430"></a><img alt="figure-g" src="/dailymed/image.cfm?name=image-08.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure G</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 6: Insert the Applicator into Rectum</span> </p> <p>Insert the applicator into your rectum as far as it is comfortable.</p> <p>The easiest way to use budesonide rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool <span class="Bold">(See Figure G)</span>.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id-999963869"></a><img alt="figure-h" src="/dailymed/image.cfm?name=figure-h.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure H</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 7: Give a Dose of Budesonide Rectal Foam</span> </p> <p>To give a dose of budesonide rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position <span class="Bold">(See Figure H)</span>.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id-534503675"></a><img alt="figure-i" src="/dailymed/image.cfm?name=figure-i.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure I</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 8: Release and Hold</span> </p> <p>Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds <span class="Bold">(See Figure I)</span>.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id-280340749"></a><img alt="figure-j" src="/dailymed/image.cfm?name=image-11.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure J</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 9: Remove the Applicator</span> </p> <p> <span class="Bold">(See Figure J)</span> </p> <p>The foam will still expand a little and may drop out of the applicator or anus.</p> </td> </tr> <tr> <td align="center" valign="top"><a name="id9188167"></a><img alt="figure-k" src="/dailymed/image.cfm?name=image-12.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure K</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 10: Remove Applicator from Canister</span> </p> <p>Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided <span class="Bold">(See Figure K)</span>. Throw the applicator throw away (disposal) bag away in your household trash.</p> </td> </tr> <tr class="Botrule Last"> <td align="center" valign="top"><a name="id539324282"></a><img alt="figure-l" src="/dailymed/image.cfm?name=image-13.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8"/><p class="First"> <span class="Bold">Figure L</span> </p> </td><td valign="top"> <p class="First"> <span class="Bold">Step 11: Twist Notch on Dome Away from Nozzle</span> </p> <p>To prevent loss of budesonide rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle <span class="Bold">(See Figure L)</span>.</p> <p> <span class="Bold">Wash your hands with soap and water after using the budesonide rectal foam. Try not to empty your bowels until the next morning.</span> </p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"50%\"/>\n<col width=\"50%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First Toprule\">\n<td align=\"center\" valign=\"top\"><a name=\"id-766929542\"></a><img alt=\"figure-b\" src=\"/dailymed/image.cfm?name=image-03.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure B</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 1: Twist Safety Tab to Remove</span>\n</p>\n<p>Before the first use, remove the safety tab from under the pump dome <span class=\"Bold\">(See Figure B)</span>.</p>\n<p>\n<span class=\"Bold\">The canister cannot be used if safety tab is not removed.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id-263762878\"></a><img alt=\"figure-c\" src=\"/dailymed/image.cfm?name=image-04.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure C</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 2: Attach the Applicator</span>\n</p>\n<p>The applicators are in a tray. Hold the tray firmly and pull to remove 1 applicator.</p>\n<p>Push the applicator firmly onto the nozzle of the canister <span class=\"Bold\">(See Figure C)</span>. Each applicator is coated with a lubricant. If needed, you can apply an additional lubricant, such as Vaseline (petrolatum, petroleum jelly).</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id774825072\"></a><img alt=\"figure-d\" src=\"/dailymed/image.cfm?name=figure-d.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure D</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 3: Align Notch to Nozzle</span>\n</p>\n<p>To unlock the canister, twist the dome on the top of the canister until the semicircular notch underneath the dome is in line with the nozzle <span class=\"Bold\">(See Figure D)</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id1223788368\"></a><img alt=\"figure-e\" src=\"/dailymed/image.cfm?name=figure-e.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure E</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 4: Warm and Shake Canister</span>\n</p>\n<p>Warm the canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds <span class=\"Bold\">(See Figure E)</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id-1605415638\"></a><img alt=\"figure-f\" src=\"/dailymed/image.cfm?name=image-07.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure F</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 5: Turn the Canister Upside Down</span>\n</p>\n<p>Place your pointer finger (forefinger) on the top of pump dome and then turn the canister upside down <span class=\"Bold\">(See Figure F)</span>.</p>\n<p>\n<span class=\"Bold\">The canister will only work properly when held with the pump dome pointing down.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id164215430\"></a><img alt=\"figure-g\" src=\"/dailymed/image.cfm?name=image-08.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure G</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 6: Insert the Applicator into Rectum</span>\n</p>\n<p>Insert the applicator into your rectum as far as it is comfortable.</p>\n<p>The easiest way to use budesonide rectal foam is to keep 1 foot on the floor and raise the other foot onto a firm surface such as a chair or stool <span class=\"Bold\">(See Figure G)</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id-999963869\"></a><img alt=\"figure-h\" src=\"/dailymed/image.cfm?name=figure-h.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure H</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 7: Give a Dose of Budesonide Rectal Foam</span>\n</p>\n<p>To give a dose of budesonide rectal foam, use your pointer finger (forefinger) to fully push down the pump dome 1 time and hold it for about 2 seconds in that position <span class=\"Bold\">(See Figure H)</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id-534503675\"></a><img alt=\"figure-i\" src=\"/dailymed/image.cfm?name=figure-i.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure I</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 8: Release and Hold</span>\n</p>\n<p>Release finger pressure on the pump dome and hold the applicator in place for 10 to 15 seconds <span class=\"Bold\">(See Figure I)</span>.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id-280340749\"></a><img alt=\"figure-j\" src=\"/dailymed/image.cfm?name=image-11.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure J</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 9: Remove the Applicator</span>\n</p>\n<p>\n<span class=\"Bold\">(See Figure J)</span>\n</p>\n<p>The foam will still expand a little and may drop out of the applicator or anus.</p>\n</td>\n</tr>\n<tr>\n<td align=\"center\" valign=\"top\"><a name=\"id9188167\"></a><img alt=\"figure-k\" src=\"/dailymed/image.cfm?name=image-12.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure K</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 10: Remove Applicator from Canister</span>\n</p>\n<p>Remove the applicator from the canister and place the used applicator in the applicator throw away (disposal) bag provided <span class=\"Bold\">(See Figure K)</span>. Throw the applicator throw away (disposal) bag away in your household trash.</p>\n</td>\n</tr>\n<tr class=\"Botrule Last\">\n<td align=\"center\" valign=\"top\"><a name=\"id539324282\"></a><img alt=\"figure-l\" src=\"/dailymed/image.cfm?name=image-13.jpg&amp;setid=ad4a68e7-9200-4f05-8058-714d5d8900f8\"/><p class=\"First\">\n<span class=\"Bold\">Figure L</span>\n</p>\n</td><td valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Step 11: Twist Notch on Dome Away from Nozzle</span>\n</p>\n<p>To prevent loss of budesonide rectal foam from the canister between uses, turn the pump dome around so that the semicircular notch faces the opposite direction to the nozzle <span class=\"Bold\">(See Figure L)</span>.</p>\n<p>\n<span class=\"Bold\">Wash your hands with soap and water after using the budesonide rectal foam. Try not to empty your bowels until the next morning.</span>\n</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

Manufactured By Padagis Yeruham 8050315, Israel

{ "type": "p", "children": [], "text": "Manufactured By Padagis Yeruham 8050315, Israel" }

Distributed By PadagisAllegan, MI 49010 • www.padagis.com

{ "type": "p", "children": [], "text": "Distributed By PadagisAllegan, MI 49010 • www.padagis.com" }

Revised: 06/2022 5Q200 RC J2

{ "type": "p", "children": [], "text": "Revised: 06/2022 5Q200 RC J2" }

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

{ "type": "p", "children": [], "text": "This Instructions for Use has been approved by the U.S. Food and Drug Administration." }

<div class="scrollingtable"><table width="100%"> <col width="100%"/> <tbody class="Headless"> <tr class="First"> <td align="center" class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">Patient Information</span> </p> <p> <span class="Bold">Budesonide (bue-DES-oh-nide)</span> </p> <p> <span class="Bold">rectal foam</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What is Budesonide rectal foam?</span> </p> <dl> <dt>•</dt> <dd>Budesonide rectal foam is a prescription corticosteroid medicine used to help get mild to moderate active ulcerative colitis that extends from the rectum to the sigmoid colon under control (induce remission). </dd> <dt>•</dt> <dd>It is not known if budesonide rectal foam is safe and effective in children.</dd> </dl> <p>It is not known if budesonide rectal foam is safe and effective in children.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">Who should not use budesonide rectal foam?</span> </p> <p>Do not use budesonide rectal foam if you are allergic to budesonide or any of the ingredients in budesonide rectal foam. See the end of this leaflet for a complete list of ingredients in budesonide rectal foam.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I tell my healthcare provider before using budesonide rectal foam?</span> </p> <p> <span class="Bold">Before you use budesonide rectal foam, tell your healthcare provider about all of your medical conditions, including if you:</span> </p> <dl> <dt>•</dt> <dd>have liver problems. </dd> <dt>•</dt> <dd>are planning to have surgery. </dd> <dt>•</dt> <dd>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </dd> <dt>•</dt> <dd>have an infection. </dd> <dt>•</dt> <dd>have or had a family history of diabetes, cataracts or glaucoma. </dd> <dt>•</dt> <dd>have or had tuberculosis. </dd> <dt>•</dt> <dd>have high blood pressure (hypertension). </dd> <dt>•</dt> <dd>have decreased bone mineral density (osteoporosis). </dd> <dt>•</dt> <dd>have stomach ulcers. </dd> <dt>•</dt> <dd>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </dd> <dt>•</dt> <dd>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</dd> </dl> <p>are planning to have surgery. </p> <p>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </p> <p>have an infection. </p> <p>have or had a family history of diabetes, cataracts or glaucoma. </p> <p>have or had tuberculosis. </p> <p>have high blood pressure (hypertension). </p> <p>have decreased bone mineral density (osteoporosis). </p> <p>have stomach ulcers. </p> <p>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </p> <p>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</p> <p> <span class="Bold">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide rectal foam and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma.</p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I use budesonide rectal foam?</span> </p> <p> <span class="Bold">See the “Instructions for Use” at the end of this Patient Information for detailed information about the right way to use budesonide rectal foam.</span> </p> <dl> <dt>•</dt> <dd>Use budesonide rectal foam exactly as your healthcare provider tells you to use it. </dd> <dt>•</dt> <dd> <span class="Bold">Budesonide rectal foam should only be used rectally (through the anus). Do not</span> take budesonide rectal foam by mouth. </dd> <dt>•</dt> <dd>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </dd> <dt>•</dt> <dd>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). <br/>After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </dd> <dt>•</dt> <dd>If you use too much budesonide rectal foam, call your healthcare provider right away. </dd> <dt>•</dt> <dd>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</dd> </dl> <p> <span class="Bold">Budesonide rectal foam should only be used rectally (through the anus). Do not</span> take budesonide rectal foam by mouth. </p> <p>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </p> <p>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). <br/>After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </p> <p>If you use too much budesonide rectal foam, call your healthcare provider right away. </p> <p>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What should I avoid while using budesonide rectal foam?</span> </p> <dl> <dt>•</dt> <dd>Do not eat grapefruit or drink grapefruit juice while using budesonide rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide rectal foam in your blood. </dd> <dt>•</dt> <dd>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</dd> </dl> <p>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">What are the possible side effects of budesonide rectal foam?</span> </p> <p> <span class="Bold">Budesonide rectal foam may cause serious side effects, including:</span> </p> <dl> <dt>•</dt> <dd> <span class="Bold">Effects of having too much corticosteroid medicine in your blood (hypercorticism).</span> Long-time use of budesonide rectal foam can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: <dl> <dt>o</dt> <dd>acne </dd> <dt>o</dt> <dd>bruise easily </dd> <dt>o</dt> <dd>rounding of your face (moon face) </dd> <dt>o</dt> <dd>ankle swelling </dd> <dt>o</dt> <dd>thicker or more hair on your body and face </dd> <dt>o</dt> <dd>a fatty pad or hump between your shoulders (buffalo hump) </dd> <dt>o</dt> <dd>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Adrenal suppression.</span> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: <dl> <dt>o</dt> <dd>tiredness </dd> <dt>o</dt> <dd>weakness </dd> <dt>o</dt> <dd>nausea </dd> <dt>o</dt> <dd>vomiting</dd> <dt>o</dt> <dd>low blood pressure</dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Immune system effects and a higher chance of infections.</span> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</dd> </dl> <p>acne </p> <p>bruise easily </p> <p>rounding of your face (moon face) </p> <p>ankle swelling </p> <p>thicker or more hair on your body and face </p> <p>a fatty pad or hump between your shoulders (buffalo hump) </p> <p>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </p> <p> <span class="Bold">Adrenal suppression.</span> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: </p> <p>tiredness </p> <p>weakness </p> <p>nausea </p> <p>vomiting</p> <p>low blood pressure</p> <p> <span class="Bold">Immune system effects and a higher chance of infections.</span> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</p> <p>Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide rectal foam, including: </p> <dl> <dt> </dt> <dd> <dl> <dt>o</dt> <dd>fever </dd> <dt>o</dt> <dd>chills </dd> <dt>o</dt> <dd>aches </dd> <dt>o</dt> <dd>feeling tired </dd> <dt>o</dt> <dd>pain </dd> <dt>o</dt> <dd>nausea or vomiting</dd> </dl> </dd> <dt>•</dt> <dd> <span class="Bold">Worsening of allergies.</span> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</dd> </dl> <p>fever </p> <p>chills </p> <p>aches </p> <p>feeling tired </p> <p>pain </p> <p>nausea or vomiting</p> <p> <span class="Bold">Worsening of allergies.</span> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</p> <p>The most common side effects of budesonide rectal foam include:</p> <dl> <dt>•</dt> <dd>decreased blood cortisol levels </dd> <dt>•</dt> <dd>adrenal insufficiency </dd> <dt>•</dt> <dd>nausea</dd> </dl> <p>adrenal insufficiency </p> <p>nausea</p> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of budesonide rectal foam. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">How should I store budesonide rectal foam?</span> </p> <dl> <dt>•</dt> <dd>Store budesonide rectal foam at room temperature, between 68°F to 77°F (20°C to 25°C). </dd> <dt>•</dt> <dd>Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). </dd> <dt>•</dt> <dd>Do not puncture or burn the budesonide rectal foam canister. </dd> <dt>•</dt> <dd>Do not refrigerate.</dd> </dl> <p>Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). </p> <p>Do not puncture or burn the budesonide rectal foam canister. </p> <p>Do not refrigerate.</p> <p> <span class="Bold">Keep budesonide rectal foam and all medicines out of the reach of children.</span> </p> </td> </tr> <tr> <td class="Botrule Lrule Rrule" valign="top"> <p class="First"> <span class="Bold">General information about the safe and effective use of budesonide rectal foam.</span> </p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide rectal foam for a condition for which it was not prescribed. Do not give budesonide rectal foam to other people, even if they have the same symptoms you have. It may harm them.</p> <p>This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about budesonide rectal foam that is written for health professionals.</p> <p>For more information, go to <span class="Bold">www.padagis.com</span> </p> </td> </tr> <tr class="Last"> <td class="Botrule Lrule Rrule Toprule" valign="top"> <p class="First"> <span class="Bold">What are the ingredients in budesonide rectal foam?</span> </p> <p> <span class="Bold">Active ingredient:</span> budesonide</p> <p> <span class="Bold">Inactive ingredients:</span> cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water</p> <p> <span class="Bold">Propellant:</span> n-butane, isobutane, and propane</p> <p>Manufactured by Padagis, Yeruham 8050315, Israel</p> <p>Distributed By Padagis, Allegan, MI 49010</p> <p>www.padagis.com</p> </td> </tr> </tbody> </table></div>

{ "type": "table", "children": [], "text": "<div class=\"scrollingtable\"><table width=\"100%\">\n<col width=\"100%\"/>\n<tbody class=\"Headless\">\n<tr class=\"First\">\n<td align=\"center\" class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Patient Information</span>\n</p>\n<p>\n<span class=\"Bold\">Budesonide (bue-DES-oh-nide)</span>\n</p>\n<p>\n<span class=\"Bold\">rectal foam</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What is Budesonide rectal foam?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Budesonide rectal foam is a prescription corticosteroid medicine used to help get mild to moderate active ulcerative colitis that extends from the rectum to the sigmoid colon under control (induce remission). </dd>\n<dt>•</dt>\n<dd>It is not known if budesonide rectal foam is safe and effective in children.</dd>\n</dl>\n<p>It is not known if budesonide rectal foam is safe and effective in children.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">Who should not use budesonide rectal foam?</span>\n</p>\n<p>Do not use budesonide rectal foam if you are allergic to budesonide or any of the ingredients in budesonide rectal foam. See the end of this leaflet for a complete list of ingredients in budesonide rectal foam.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I tell my healthcare provider before using budesonide rectal foam?</span>\n</p>\n<p>\n<span class=\"Bold\">Before you use budesonide rectal foam, tell your healthcare provider about all of your medical conditions, including if you:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>have liver problems. </dd>\n<dt>•</dt>\n<dd>are planning to have surgery. </dd>\n<dt>•</dt>\n<dd>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </dd>\n<dt>•</dt>\n<dd>have an infection. </dd>\n<dt>•</dt>\n<dd>have or had a family history of diabetes, cataracts or glaucoma. </dd>\n<dt>•</dt>\n<dd>have or had tuberculosis. </dd>\n<dt>•</dt>\n<dd>have high blood pressure (hypertension). </dd>\n<dt>•</dt>\n<dd>have decreased bone mineral density (osteoporosis). </dd>\n<dt>•</dt>\n<dd>have stomach ulcers. </dd>\n<dt>•</dt>\n<dd>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </dd>\n<dt>•</dt>\n<dd>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</dd>\n</dl>\n<p>are planning to have surgery. </p>\n<p>have chicken pox or measles or have recently been near anyone with chicken pox or measles. </p>\n<p>have an infection. </p>\n<p>have or had a family history of diabetes, cataracts or glaucoma. </p>\n<p>have or had tuberculosis. </p>\n<p>have high blood pressure (hypertension). </p>\n<p>have decreased bone mineral density (osteoporosis). </p>\n<p>have stomach ulcers. </p>\n<p>are pregnant or plan to become pregnant. Budesonide rectal foam may harm your unborn baby. Tell your healthcare provider if you are pregnant or think you are pregnant. </p>\n<p>are breastfeeding or plan to breastfeed. Budesonide can pass into your breast milk and may harm your baby. You and your healthcare provider should decide if you will use budesonide rectal foam or breastfeed. You should not do both.</p>\n<p>\n<span class=\"Bold\">Tell your healthcare provider about all the medicines you take,</span> including prescription and over-the-counter medicines, vitamins, and herbal supplements. Budesonide rectal foam and other medicines may affect each other causing side effects. Especially tell your healthcare provider if you take another medicine that contains corticosteroids for other conditions, such as allergies or asthma.</p>\n<p>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I use budesonide rectal foam?</span>\n</p>\n<p>\n<span class=\"Bold\">See the “Instructions for Use” at the end of this Patient Information for detailed information about the right way to use budesonide rectal foam.</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Use budesonide rectal foam exactly as your healthcare provider tells you to use it. </dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Budesonide rectal foam should only be used rectally (through the anus). Do not</span> take budesonide rectal foam by mouth. </dd>\n<dt>•</dt>\n<dd>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </dd>\n<dt>•</dt>\n<dd>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). <br/>After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </dd>\n<dt>•</dt>\n<dd>If you use too much budesonide rectal foam, call your healthcare provider right away. </dd>\n<dt>•</dt>\n<dd>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</dd>\n</dl>\n<p>\n<span class=\"Bold\">Budesonide rectal foam should only be used rectally (through the anus). Do not</span> take budesonide rectal foam by mouth. </p>\n<p>Warm the budesonide rectal foam canister by holding it in your hands while shaking it vigorously for 10 to 15 seconds. </p>\n<p>Budesonide rectal foam is used twice a day for the first 2 weeks of treatment (in the morning and in the evening). <br/>After 2 weeks, use budesonide rectal foam 1 time a day in the evening, before bedtime for 4 weeks. </p>\n<p>If you use too much budesonide rectal foam, call your healthcare provider right away. </p>\n<p>You should stop using budesonide rectal foam before preparing for a colonoscopy. Call your healthcare provider before restarting budesonide rectal foam after your colonoscopy.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What should I avoid while using budesonide rectal foam?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Do not eat grapefruit or drink grapefruit juice while using budesonide rectal foam. Eating grapefruit or drinking grapefruit juice can increase the level of budesonide rectal foam in your blood. </dd>\n<dt>•</dt>\n<dd>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</dd>\n</dl>\n<p>Budesonide rectal foam is flammable. Avoid fire, flame and smoking during and right after using budesonide rectal foam.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the possible side effects of budesonide rectal foam?</span>\n</p>\n<p>\n<span class=\"Bold\">Budesonide rectal foam may cause serious side effects, including:</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Effects of having too much corticosteroid medicine in your blood (hypercorticism).</span> Long-time use of budesonide rectal foam can cause you to have too much glucocorticosteroid medicine in your blood. Tell your healthcare provider if you have any of the following signs and symptoms of hypercorticism: <dl>\n<dt>o</dt>\n<dd>acne </dd>\n<dt>o</dt>\n<dd>bruise easily </dd>\n<dt>o</dt>\n<dd>rounding of your face (moon face) </dd>\n<dt>o</dt>\n<dd>ankle swelling </dd>\n<dt>o</dt>\n<dd>thicker or more hair on your body and face </dd>\n<dt>o</dt>\n<dd>a fatty pad or hump between your shoulders (buffalo hump) </dd>\n<dt>o</dt>\n<dd>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Adrenal suppression.</span> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: <dl>\n<dt>o</dt>\n<dd>tiredness </dd>\n<dt>o</dt>\n<dd>weakness </dd>\n<dt>o</dt>\n<dd>nausea </dd>\n<dt>o</dt>\n<dd>vomiting</dd>\n<dt>o</dt>\n<dd>low blood pressure</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Immune system effects and a higher chance of infections.</span> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</dd>\n</dl>\n<p>acne </p>\n<p>bruise easily </p>\n<p>rounding of your face (moon face) </p>\n<p>ankle swelling </p>\n<p>thicker or more hair on your body and face </p>\n<p>a fatty pad or hump between your shoulders (buffalo hump) </p>\n<p>pink or purple stretch marks on the skin of your abdomen, thighs, breasts and arms </p>\n<p>\n<span class=\"Bold\">Adrenal suppression.</span> When budesonide rectal foam is used for a long period of time (chronic use), the adrenal glands may not make enough steroid hormones (adrenal suppression). Tell your healthcare provider if you are under stress or have any symptoms of adrenal suppression during treatment with budesonide rectal foam including: </p>\n<p>tiredness </p>\n<p>weakness </p>\n<p>nausea </p>\n<p>vomiting</p>\n<p>low blood pressure</p>\n<p>\n<span class=\"Bold\">Immune system effects and a higher chance of infections.</span> Budesonide rectal foam may weaken your immune system. Taking medicines that weaken your immune system makes you more likely to get infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using budesonide rectal foam.</p>\n<p>Tell your healthcare provider about any signs or symptoms of infection during treatment with budesonide rectal foam, including: </p>\n<dl>\n<dt> </dt>\n<dd>\n<dl>\n<dt>o</dt>\n<dd>fever </dd>\n<dt>o</dt>\n<dd>chills </dd>\n<dt>o</dt>\n<dd>aches </dd>\n<dt>o</dt>\n<dd>feeling tired </dd>\n<dt>o</dt>\n<dd>pain </dd>\n<dt>o</dt>\n<dd>nausea or vomiting</dd>\n</dl>\n</dd>\n<dt>•</dt>\n<dd>\n<span class=\"Bold\">Worsening of allergies.</span> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</dd>\n</dl>\n<p>fever </p>\n<p>chills </p>\n<p>aches </p>\n<p>feeling tired </p>\n<p>pain </p>\n<p>nausea or vomiting</p>\n<p>\n<span class=\"Bold\">Worsening of allergies.</span> If you take certain other corticosteroid medicines to treat allergies, switching to budesonide rectal foam may cause your allergies to come back. These allergies may include eczema (a skin disease) or inflammation inside your nose (rhinitis). Tell your healthcare provider if any of your allergies become worse while using budesonide rectal foam.</p>\n<p>The most common side effects of budesonide rectal foam include:</p>\n<dl>\n<dt>•</dt>\n<dd>decreased blood cortisol levels </dd>\n<dt>•</dt>\n<dd>adrenal insufficiency </dd>\n<dt>•</dt>\n<dd>nausea</dd>\n</dl>\n<p>adrenal insufficiency </p>\n<p>nausea</p>\n<p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p>\n<p>These are not all the possible side effects of budesonide rectal foam. For more information, ask your healthcare provider or pharmacist.</p>\n<p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">How should I store budesonide rectal foam?</span>\n</p>\n<dl>\n<dt>•</dt>\n<dd>Store budesonide rectal foam at room temperature, between 68°F to 77°F (20°C to 25°C). </dd>\n<dt>•</dt>\n<dd>Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). </dd>\n<dt>•</dt>\n<dd>Do not puncture or burn the budesonide rectal foam canister. </dd>\n<dt>•</dt>\n<dd>Do not refrigerate.</dd>\n</dl>\n<p>Do not store the budesonide rectal foam container near heat or store at temperatures above 120°F (49°C). </p>\n<p>Do not puncture or burn the budesonide rectal foam canister. </p>\n<p>Do not refrigerate.</p>\n<p>\n<span class=\"Bold\">Keep budesonide rectal foam and all medicines out of the reach of children.</span>\n</p>\n</td>\n</tr>\n<tr>\n<td class=\"Botrule Lrule Rrule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">General information about the safe and effective use of budesonide rectal foam.</span>\n</p>\n<p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use budesonide rectal foam for a condition for which it was not prescribed. Do not give budesonide rectal foam to other people, even if they have the same symptoms you have. It may harm them.</p>\n<p>This Patient Information leaflet summarizes the most important information about budesonide rectal foam. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about budesonide rectal foam that is written for health professionals.</p>\n<p>For more information, go to <span class=\"Bold\">www.padagis.com</span>\n</p>\n</td>\n</tr>\n<tr class=\"Last\">\n<td class=\"Botrule Lrule Rrule Toprule\" valign=\"top\">\n<p class=\"First\">\n<span class=\"Bold\">What are the ingredients in budesonide rectal foam?</span>\n</p>\n<p>\n<span class=\"Bold\">Active ingredient:</span> budesonide</p>\n<p>\n<span class=\"Bold\">Inactive ingredients:</span> cetyl alcohol, citric acid monohydrate, edetate disodium, emulsifying wax, polyoxyl (10) stearyl ether, propylene glycol, and purified water</p>\n<p>\n<span class=\"Bold\">Propellant:</span> n-butane, isobutane, and propane</p>\n<p>Manufactured by Padagis, Yeruham 8050315, Israel</p>\n<p>Distributed By Padagis, Allegan, MI 49010</p>\n<p>www.padagis.com</p>\n</td>\n</tr>\n</tbody>\n</table></div>" }

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2022

{ "type": "p", "children": [], "text": "This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2022" }

Rx Only

{ "type": "p", "children": [], "text": "Rx Only" }

Budesonide Rectal Foam, 2 mg/actuation

{ "type": "p", "children": [], "text": "Budesonide Rectal Foam, 2 mg/actuation" }

For rectal administration only, as directed by a physician.

{ "type": "p", "children": [], "text": "For rectal administration only, as directed by a physician." }

Shake well before using.

{ "type": "p", "children": [], "text": "Shake well before using." }

Each canister contains 14 metered doses.

{ "type": "p", "children": [], "text": "Each canister contains 14 metered doses." }

Net weight 33.4 g per canister.

{ "type": "p", "children": [], "text": "Net weight 33.4 g per canister." }

The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation.

{ "type": "p", "children": [], "text": "The following image is a placeholder representing the product identifier that is either affixed or imprinted on the drug package label during the packaging operation." }

RHINOCORT AQUA Nasal Spray is indicated for the treatment of nasal symptoms of seasonal or perennial allergic rhinitis in adults and children six years of age and older.

The recommended starting dosage for adults and children 6 years of age and older is 64 mcg per day administered as one spray per nostril of RHINOCORT AQUA Nasal Spray 32 mcg once daily. Some patients who do not achieve symptom control at the recommended starting dosage may benefit from an increased dosage. The maximum recommended dosage for adults (12 years of age and older) is 256 mcg per day administered as four sprays per nostril once daily of RHINOCORT AQUA Nasal Spray 32 mcg and the maximum recommended dose for pediatric patients (6 to <12 years of age) is 128 mcg per day administered as two sprays per nostril once daily of RHINOCORT AQUA Nasal Spray 32 mcg.

{ "type": "p", "children": [], "text": "The recommended starting dosage for adults and children 6 years of age and older is 64 mcg per day administered as one spray per nostril of RHINOCORT AQUA Nasal Spray 32 mcg once daily. Some patients who do not achieve symptom control at the recommended starting dosage may benefit from an increased dosage. The maximum recommended dosage for adults (12 years of age and older) is 256 mcg per day administered as four sprays per nostril once daily of RHINOCORT AQUA Nasal Spray 32 mcg and the maximum recommended dose for pediatric patients (6 to <12 years of age) is 128 mcg per day administered as two sprays per nostril once daily of RHINOCORT AQUA Nasal Spray 32 mcg." }

It is always desirable to titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects. An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray, however, clinical improvement usually takes 1-2 days with maximum benefit in approximately 2 weeks. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage may be effective in maintaining control of the allergic rhinitis symptoms in patients who were initially controlled on higher dosages.

{ "type": "p", "children": [], "text": "It is always desirable to titrate an individual patient to the minimum effective dosage to reduce the possibility of side effects. An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray, however, clinical improvement usually takes 1-2 days with maximum benefit in approximately 2 weeks. When the maximum benefit has been achieved and symptoms have been controlled, reducing the dosage may be effective in maintaining control of the allergic rhinitis symptoms in patients who were initially controlled on higher dosages." }

Prior to initial use, the container must be shaken gently and the pump must be primed by actuating eight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears. Shake the container gently before each use.

{ "type": "p", "children": [], "text": "Prior to initial use, the container must be shaken gently and the pump must be primed by actuating eight times. If used daily, the pump does not need to be reprimed. If not used for two consecutive days, reprime with one spray or until a fine spray appears. If not used for more than 14 days, rinse the applicator and reprime with two sprays or until a fine spray appears. Shake the container gently before each use." }

Illustrated Patient’s Instructions for Use accompany each package of RHINOCORT AQUA 32 mcg.

{ "type": "p", "children": [], "text": "Illustrated Patient’s Instructions for Use accompany each package of RHINOCORT AQUA 32 mcg." }

RHINOCORT AQUA Nasal Spray is a nasal spray suspension. Each spray delivers 32 mcg of budesonide. Each bottle of RHINOCORT AQUA Nasal Spray 32 mcg contains 120 metered sprays after initial priming.

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray is a nasal spray suspension. Each spray delivers 32 mcg of budesonide. Each bottle of RHINOCORT AQUA Nasal Spray 32 mcg contains 120 metered sprays after initial priming." }

RHINOCORT AQUA Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.2)].

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray is contraindicated in patients with hypersensitivity to any of its ingredients [see Warnings and Precautions (5.2)]." }

Epistaxis

In clinical studies of 3 to 52 weeks’ duration epistaxis was observed more frequently in patients treated with RHINOCORT AQUA Nasal Spray than those who received placebo [see Adverse Reactions (6.1)].

Candida Infection

In clinical studies with budesonide administered intranasally, the development of localized infections of the nose and pharynx with Candida albicans has occurred. When such an infection develops, it may require treatment with appropriate local or systemic therapy and discontinuation of treatment with RHINOCORT AQUA Nasal Spray. Patients using RHINOCORT AQUA Nasal Spray over several months or longer should be examined periodically for evidence of Candida infection or other signs of adverse effects on the nasal mucosa.

Nasal Septal Perforation

Instances of nasal septum perforation have been reported following the intranasal application of corticosteroids, including budesonide [see Adverse Reactions (6.2)].

Impaired Wound Healing

Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use a nasal corticosteroid until healing has occurred.

Hypersensitivity reactions including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus may occur [see Contraindications (4) and Adverse Reactions, Post-marketing Experience (6.2)].

Patients who are on drugs that suppress the immune system are more susceptible to infections 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 such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered.

The clinical course of chicken pox or measles infection in patients on intranasal or inhaled corticosteroids has not been studied. While there is no data with intranasal corticosteroids, a clinical study has examined the immune responsiveness to the varicella vaccine in asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension.

An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., beta2-agonists, leukotriene receptor antagonists, or cromones). The percentage of patients developing a seroprotective antibody titer ≥ 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-corticosteroids asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections; or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: When intranasal steroids are used at higher than recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of RHINOCORT AQUA Nasal Spray should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency, and in addition some patients may experience symptoms of corticosteroid withdrawal, e.g., joint and/or muscular pain, fatigue, weakness, nausea, vomiting, hypotension, lassitude, and depression. Patients previously treated for prolonged periods with systemic corticosteroids should be weaned off slowly when transferred to topical corticosteroids and carefully monitored for acute adrenal insufficiency in response to stress. In those patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a decrease in systemic corticosteroids may cause a severe exacerbation of their symptoms.

Caution should be exercised when considering the co-administration of RHINOCORT AQUA Nasal Spray with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Intranasal corticosteroids, including budesonide may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth routinely of pediatric patients receiving long-term treatment with RHINOCORT AQUA Nasal Spray. To minimize the systemic effects of intranasal corticosteroids, including RHINOCORT AQUA Nasal Spray, titrate each patient’s dosage to the lowest one that effectively controls his/her symptoms [see Use in Specific Populations, Pediatric Use (8.4)].

Glaucoma, increased intraocular pressure and cataracts have been reported following the intranasal application of 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 [see Adverse Reactions (6.2)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The incidence of common adverse reactions in Table 1 is based upon two U.S. and five non-U.S. controlled clinical trials in 1,526 patients with seasonal or perennial rhinitis in adults and children ≥ 6 years treated with RHINOCORT AQUA Nasal Spray at doses up to 400 mcg once daily for 3-6 weeks. This population included 745 females and 781 males with a mean age of 31 years (range of 6-85 years, 349 were 6 < 18 years). The racial distribution of patients receiving RHINOCORT AQUA Nasal Spray was 93% white, 3% black and 4% other. Table 1 describes adverse reactions occurring at an incidence of 2% or greater and more commonly among RHINOCORT AQUA Nasal Spray-treated patients than in placebo-treated patients in controlled clinical trials.

<div class="scrollingtable"><table frame="hsides"> <caption> <span>Table 1. Adverse Reactions occurring at an incidence ≥ 2% and more commonly than placebo in the RHINOCORT AQUA Nasal Spray group in patients 6 years and older</span> </caption> <colgroup> <col align="left" valign="top"/> <col align="left" valign="top"/> <col align="left" valign="top"/> </colgroup> <thead> <tr class="Botrule First Last"> <th align="center">Adverse Event </th><th align="center">RHINOCORT AQUA Nasal Spray</th><th align="center">Placebo Vehicle</th> </tr> </thead> <tbody> <tr class="First"> <td align="left"> <p class="First">Epistaxis</p> </td><td align="center"> <p class="First">8%</p> </td><td align="center"> <p class="First">5%</p> </td> </tr> <tr> <td align="left"> <p class="First">Pharyngitis</p> </td><td align="center"> <p class="First">4%</p> </td><td align="center"> <p class="First">3%</p> </td> </tr> <tr> <td align="left"> <p class="First">Bronchospasm</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">1%</p> </td> </tr> <tr> <td align="left"> <p class="First">Coughing</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">&lt;1%</p> </td> </tr> <tr class="Last"> <td align="left"> <p class="First">Nasal Irritation</p> </td><td align="center"> <p class="First">2%</p> </td><td align="center"> <p class="First">&lt;1%</p> </td> </tr> </tbody> </table></div>

A similar adverse reaction profile was observed in the subgroup of pediatric patients 6 to 12 years of age. These patients are included in Table 1.

Two to three percent (2-3%) of patients in clinical trials discontinued because of adverse reactions. Systemic corticosteroid side effects were not reported during controlled clinical studies with RHINOCORT AQUA Nasal Spray.

If recommended doses are exceeded, or if individuals are particularly sensitive, symptoms of hypercorticism, ie, Cushing’s Syndrome, and adrenal suppression could occur.

The following adverse reactions have been reported during post-approval use of RHINOCORT AQUA Nasal Spray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: immediate and delayed hypersensitivity reactions (including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus), [see Warnings and Precautions (5.2) and Contraindications (4)]

Eye disorders: glaucoma, increased intraocular pressure, cataracts [see Warnings and Precautions (5.7)]

Respiratory, thoracic, and mediastinal disorders: nasal septum perforation, anosmia, pharynx disorders (throat irritation, throat pain, swollen throat, burning throat, and itchy throat), and wheezing

Cardiac disorders: palpitations

Musculoskeletal and connective tissue disorders: growth suppression [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]

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 CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the co-administration of RHINOCORT AQUA Nasal Spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

Teratogenic Effects: Pregnancy Category B. The impact of budesonide on human pregnancy outcomes has been evaluated through assessments of birth registries linked with maternal usage of inhaled budesonide (i.e., PULMICORT TURBUHALER) and intranasally administered budesonide (i.e., RHINOCORT AQUA Nasal Spray). The results from population-based prospective cohort epidemiological studies reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995- 2001 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for overall congenital malformations from the use of inhaled or intranasal 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.1 The rate of overall congenital malformations was similar compared to the general population rate (3.8 % vs. 3.5%, respectively). The number of infants born with orofacial clefts and cardiac defects was similar to the expected number in the general population (4 children vs. 3.3 and 18 children vs. 17-18, respectively). In a follow-on study bringing the total number of infants to 2,534, the rate of overall 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%).2 A third study from the Swedish Medical Birth Registry of 2,968 pregnancies exposed to inhaled budesonide, the majority of which were first trimester exposures, reported gestational age, birth weight, birth length, stillbirths, and multiple births similar for exposed infants compared to nonexposed infants.3

Congenital malformations were studied in 2,113 infants born to mothers reporting the use of intranasal budesonide in early pregnancy. The rate of overall congenital malformations was similar compared to the general population rate (4.5% vs. 3.5%, respectively). The adjusted odds ratio (OR) was 1.06 (95% CI 0.86-1.31). The number of infants born with orofacial clefts was similar to the expected number in the general population (3 children vs. 3, respectively). The number of infants born with cardiac defects exceeded that expected in the general population (28 children vs. 17.8 respectively). The systemic exposure from intranasal budesonide is 6-fold less than from inhaled budesonide and an association of cardiac defects was not seen with higher exposures of budesonide.

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, RHINOCORT AQUA Nasal Spray should be used during pregnancy only if clearly needed.

Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis and at a subcutaneous dose in rats that was approximately 16 times the maximum recommended daily intranasal 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 8 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis.

Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Budesonide is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology, Pharmacokinetics, Special Populations, Nursing (12.3)]. No studies have been conducted in breastfeeding women specifically with RHINOCORT AQUA Nasal Spray; 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. RHINOCORT AQUA Nasal Spray should be used in nursing women only if clinically appropriate. Prescribers should weigh the known benefits of breastfeeding for the mother and 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 RHINOCORT AQUA Nasal Spray immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure.

Safety and effectiveness in pediatric patients below 6 years of age have not been established.

Controlled clinical studies have shown that intranasal 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 intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied.

The growth of pediatric patients receiving intranasal corticosteroids, including RHINOCORT AQUA Nasal Spray, 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 intranasal corticosteroids, including RHINOCORT AQUA Nasal Spray, each patient should be titrated to the lowest dose that effectively controls his/her symptoms.

A one-year placebo-controlled clinical growth study was conducted in 229 pediatric patients (ages 4 through 8 years of age) to assess the effect of RHINOCORT AQUA Nasal Spray (single-daily dose of 64 mcg, the recommended starting dose for children ages 6 years and above) on growth velocity. From a population of 141 patients receiving RHINOCORT AQUA Nasal Spray and 67 receiving placebo, the point estimate for growth velocity with RHINOCORT AQUA Nasal Spray was 0.25 cm/year lower than that noted with placebo (95% confidence interval ranging from 0.59 cm/year lower than placebo to 0.08 cm/year higher than placebo).

In a study of asthmatic children 5-12 years of age, those treated with budesonide administered via a dry powder inhaler 200 mcg twice daily (n=311) had a 1.1-centimeter (0.433 inch) 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 budesonide dry powder inhaler and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.

The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children, systemic exposure to budesonide at the highest recommended doses of RHINOCORT AQUA Nasal Spray would be expected to be no greater than exposure at the lowest recommended doses via a dry powder inhaler. Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from RHINOCORT AQUA Nasal Spray would be expected to be no greater than what is reported for inhaled budesonide when administered via the dry powder inhaler.

The potential for RHINOCORT AQUA Nasal Spray to cause growth suppression in susceptible patients or when given at doses above 64 mcg daily cannot be ruled out. The recommended dosage range in patients 6 to 11 years of age is 64 to 128 mcg per day [see Dosage and Administration (2)].

Of the 2,461 patients in clinical studies of RHINOCORT AQUA Nasal Spray, 5% were 60 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, except for an adverse reaction reporting frequency of epistaxis that increased with age. Further, other reported clinical experience has not identified any other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Formal pharmacokinetic studies using RHINOCORT AQUA Nasal Spray have not been conducted in patients with hepatic impairment. However, since budesonide is predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide in plasma. Therefore, patients with hepatic disease should be closely monitored.

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 clinical significance of this is unknown.

The activity of RHINOCORT AQUA Nasal Spray 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 seasonal and perennial allergic rhinitis is not well known. Inflammation is an important component in the pathogenesis of seasonal and perennial allergic rhinitis. 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 seasonal and perennial allergic rhinitis.

A 3-week clinical study in seasonal rhinitis, comparing RHINOCORT Nasal Inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of RHINOCORT Nasal Inhaler can be attributed to the topical effects of budesonide.

HPA Axis Effects:

The effects of RHINOCORT AQUA Nasal Spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily of RHINOCORT AQUA Nasal Spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to 12 months.

After treatment with the recommended maximal daily dose of RHINOCORT AQUA Nasal Spray (256 mcg) for seven days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24h) in healthy adult volunteers.

A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of RHINOCORT AQUA Nasal Spray doses ranging from 100-800 mcg daily for up to four days in 78 healthy adult volunteers. The clinical relevance of these results is unknown.

Absorption

After intranasal administration of a single dose of RHINOCORT AQUA Nasal Spray (128 mcg), the mean peak plasma concentration of approximately 0.3 nmol/L occurs about 0.5 hours post-dose. Compared to an intravenous dose, approximately 34% of the delivered intranasal dose reaches the systemic circulation, most of which is absorbed through the nasal mucosa. While budesonide is well absorbed from the GI tract, the oral bioavailability of budesonide is low (~10%) primarily due to extensive first pass metabolism in the liver.

Distribution

The volume of distribution of budesonide was approximately 2-3 L/kg. It was 85-90% bound to plasma proteins. The volume of distribution for the 22R epimer is almost twice that of the 22S epimer. Protein binding was constant over a concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of RHINOCORT AQUA Nasal Spray. 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 difference 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 2/3 of an intranasal radiolabeled dose was recovered in the urine and the remainder in the feces. No unchanged budesonide was detected in the urine.

Specific Populations

Geriatric

The pharmacokinetics of RHINOCORT AQUA Nasal Spray in geriatric patients have not been specifically studied.

Pediatric

Following administration of RHINOCORT AQUA Nasal Spray, the time to reach peak drug concentrations and plasma half-life were similar in children and in adults. Children had plasma concentrations approximately twice those observed in adults due primarily to differences in weight between children and adults.

Gender

No specific pharmacokinetic study has been conducted to evaluate the effect of gender on budesonide pharmacokinetics. However, following administration of 400 mcg of RHINOCORT AQUA Nasal Spray to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender differences in the pharmacokinetic parameters were found.

Race

No specific study has been undertaken to evaluate the effect of race on budesonide pharmacokinetics.

Nursing Mothers

The disposition of budesonide when delivered by oral 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 was 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 (8.3)].

Renal or Hepatic Impairment

The pharmacokinetics of budesonide have not been investigated in patients with renal impairment. 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 relevance of this finding to intranasally administered budesonide has not been established.

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 (5.5) and Drug Interactions (7.1)].

Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.

In a 104-week oral study in Sprague-Dawley rats, a statistically significant increase in the incidence of gliomas was observed in the male rats receiving an oral dose of budesonide 50 mcg/kg/day (approximately twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg (approximately equal to the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis, and in female rats at oral doses up to 50 mcg/kg approximately two times the maximum recommended daily intranasal dose in adults and children 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 twice the maximum recommended daily intranasal dose in adults and children 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 twice the maximum recommended daily intranasal dose in adults and children on a mcg/m2 basis). The concurrent reference corticosteroids (prednisolone 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 (approximately 3 times the maximum recommended daily intranasal dose in adults and children on a mcg/m2 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 (approximately 3 times the maximum recommended daily intranasal dose in adults on mcg/m2 basis).

At a subcutaneous dose of 20 mcg/kg/day (less than the maximum recommended daily intranasal dose in adults on a mcg/m2 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 daily intranasal dose in adults on a mcg/m2 basis).

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 2 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis) and at a subcutaneous dose of 500 mcg/kg in rats (approximately 16 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis). No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation doses up to 250 mcg/kg (approximately 8 times the maximum recommended daily intranasal dose in adults on a mcg/m2 basis).

The therapeutic efficacy of RHINOCORT AQUA Nasal Spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration.

{ "type": "p", "children": [], "text": "The therapeutic efficacy of RHINOCORT AQUA Nasal Spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration." }

The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian.

{ "type": "p", "children": [], "text": "The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian." }

Overall, the results of these clinical trials showed that RHINOCORT AQUA Nasal Spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion.

{ "type": "p", "children": [], "text": "Overall, the results of these clinical trials showed that RHINOCORT AQUA Nasal Spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion." }

An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients that demonstrated that RHINOCORT AQUA Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment.

{ "type": "p", "children": [], "text": "An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients that demonstrated that RHINOCORT AQUA Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment." }

1 Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93:392-395.

{ "type": "p", "children": [], "text": "\n1 Kallen B, Rydhstroem H, Aberg A. Congenital malformations after the use of inhaled budesonide in early pregnancy. Obstet Gynecol 1999; 93:392-395." }

2 Ericson A, Kallen B. Use of drugs during pregnancy: unique Swedish registration method that can be improved. Swedish Medical Products Agency 1999;1:8-11.

{ "type": "p", "children": [], "text": "\n2 Ericson A, Kallen B. Use of drugs during pregnancy: unique Swedish registration method that can be improved. Swedish Medical Products Agency 1999;1:8-11." }

3 Norjavaara E, Gerhardsson de Verdier M. Normal pregnancy outcomes in a population-based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111:736-742.

{ "type": "p", "children": [], "text": "\n3 Norjavaara E, Gerhardsson de Verdier M. Normal pregnancy outcomes in a population-based study including 2968 pregnant women exposed to budesonide. J Allergy Clin Immunol 2003;111:736-742." }

Patients should be advised that epistaxis and localized infections with Candida albicans occurred in the nose and pharynx in some patients. If candidiasis develops, it should be treated with appropriate local or systemic therapy and discontinue treatment with RHINOCORT AQUA Nasal spray. In addition, nasal corticosteroids are associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use RHINOCORT AQUA Nasal Spray until healing has occurred [see Warnings and Precautions (5.1)].

Patients should be advised that hypersensitivity reactions including anaphylactic reaction, urticaria, rash, dermatitis, angioedema and pruritus have been reported with use of RHINOCORT AQUA Nasal Spray. Discontinue RHINOCORT AQUA Nasal Spray if such reactions occur [see Contraindications (4)Warnings and Preacautions(5.2) and Adverse Reactions (6)].

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. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection, or ocular herpes simplex [see Warnings and Precautions (5.3)].

Patients should be advised that intranasal corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.7)].

Patients should be advised that long-term use of intranasal corticosteroids, including budesonide, may increase the risk of some eye problems (cataracts and glaucoma). Patients should inform his/her healthcare provider if a change in vision is noted while using RHINOCORT AQUA Nasal Spray [see Warnings and Precautions (5.7)].

Patients should use RHINOCORT AQUA Nasal Spray at regular intervals since its effectiveness depends on its regular use. Patients may note an improvement in nasal symptoms within 10 hours of first using RHINOCORT AQUA Nasal Spray. Maximum benefit may not be achieved until approximately 2 week after initiation of treatment [see Dosage and Administration (2)].

Patients should take the medication as directed and should not exceed the prescribed dosage. The patient should contact the physician if symptoms do not improve after two weeks, or if the condition worsens. Patients who experience recurrent episodes of epistaxis (nosebleeds) or nasal septum discomfort while taking this medication should contact their physician. For proper use of RHINOCORT AQUA Nasal Spray and to attain maximum improvement, the patient should read and follow the accompanying patient information carefully. Do not use RHINOCORT AQUA Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label.

Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery [see Patient Information].

All trademarks are the property of the AstraZeneca group of companies

©AstraZeneca 2008, 2009, 2010

Distributed by:

AstraZeneca LP, Wilmington, DE 19850

Rev. 12/10

Additional barcode labeling by: Physicians Total Care, Inc.Tulsa, Oklahoma       74146

RHINOCORT AQUA®

{ "type": "p", "children": [], "text": "\nRHINOCORT AQUA®\n" }

(RINE-o-cort AH-kwa)

{ "type": "p", "children": [], "text": "\n(RINE-o-cort AH-kwa)\n" }

(budesonide)

{ "type": "p", "children": [], "text": "\n(budesonide)\n" }

Nasal Spray

{ "type": "p", "children": [], "text": "\nNasal Spray\n" }

For use in your nose only

{ "type": "p", "children": [], "text": "\nFor use in your nose only\n" }

Read the Patient Information that comes with RHINOCORT AQUA Nasal Spray before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about RHINOCORT AQUA Nasal Spray, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "Read the Patient Information that comes with RHINOCORT AQUA Nasal Spray before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment. If you have questions about RHINOCORT AQUA Nasal Spray, ask your healthcare provider or pharmacist. " }

What is RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat is RHINOCORT AQUA Nasal Spray?\n" }

RHINOCORT AQUA Nasal Spray is a prescription medicine used to treat seasonal and year-round allergy symptoms in adults and children 6 years of age and older.

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray is a prescription medicine used to treat seasonal and year-round allergy symptoms in adults and children 6 years of age and older." }

RHINOCORT AQUA Nasal Spray contains budesonide, which is a man-made (synthetic) corticosteroid. Intranasal corticosteroids are natural hormones found in the body that reduce swelling of the lining of your nose. When you spray RHINOCORT AQUA Nasal Spray into your nose, it helps reduce the nasal symptoms of allergic rhinitis (inflammation of the lining of the nose), such as stuffy nose, runny nose, itching and sneezing.

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray contains budesonide, which is a man-made (synthetic) corticosteroid. Intranasal corticosteroids are natural hormones found in the body that reduce swelling of the lining of your nose. When you spray RHINOCORT AQUA Nasal Spray into your nose, it helps reduce the nasal symptoms of allergic rhinitis (inflammation of the lining of the nose), such as stuffy nose, runny nose, itching and sneezing. " }

The safety and effectiveness of RHINOCORT AQUA Nasal Spray has not been shown in children under 6 years of age.

{ "type": "p", "children": [], "text": "The safety and effectiveness of RHINOCORT AQUA Nasal Spray has not been shown in children under 6 years of age." }

Who should not use RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nWho should not use RHINOCORT AQUA Nasal Spray?\n" }

Do not use RHINOCORT AQUA Nasal Spray:

{ "type": "p", "children": [], "text": "Do not use RHINOCORT AQUA Nasal Spray:" }

· if you are allergic to budesonide or any of the ingredients in RHINOCORT AQUA Nasal Spray. See the end of this leaflet for a complete list of the ingredients in RHINOCORT AQUA Nasal Spray.

{ "type": "p", "children": [], "text": "\n · \tif you are allergic to budesonide or any of the ingredients in RHINOCORT AQUA Nasal Spray. See the end of this leaflet for a complete list of the ingredients in RHINOCORT AQUA Nasal Spray. " }

What should I tell my healthcare provider before using RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat should I tell my healthcare provider before using RHINOCORT AQUA Nasal Spray?\n" }

Before you use RHINOCORT AQUA Nasal Spray, tell your healthcare provider or pharmacist if you:

{ "type": "p", "children": [], "text": "Before you use RHINOCORT AQUA Nasal Spray, tell your healthcare provider or pharmacist if you:" }

{ "type": "ul", "children": [ "\nhave recently been around anyone with chicken pox or measles\n", "\nhave liver problems\n", "\nhave any untreated infections\n", "\nhave ever had an infection called tuberculosis\n", "\nhave an eye infection\n", "\nhave recently had surgery or an injury to your nose\n", "\nhave any other medical conditions\n", "\nare pregnant or plan to become pregnant. It is not known if RHINOCORT AQUA Nasal Spray will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.\n", "\nare breastfeeding or plan to breastfeed. RHINOCORT AQUA Nasal Spray can pass into your breast milk. Talk to your doctor about the best way to feed your baby if you take RHINOCORT AQUA Nasal Spray.\n" ], "text": "" }

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

{ "type": "p", "children": [], "text": "\nTell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. " }

RHINOCORT AQUA Nasal Spray may affect the way other medicines work, and other medicines may affect how RHINOCORT AQUA Nasal Spray works.

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray may affect the way other medicines work, and other medicines may affect how RHINOCORT AQUA Nasal Spray works. " }

Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine.

{ "type": "p", "children": [], "text": "Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine. " }

How should I use RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow should I use RHINOCORT AQUA Nasal Spray?\n" }

{ "type": "ul", "children": [ "\nRHINOCORT AQUA Nasal Spray is for use in your nose only. Do not spray it in your eyes or mouth.\n", "\nUse RHINOCORT AQUA Nasal Spray exactly as your healthcare provider tells you to use it. \n", "\nIt is very important that you use RHINOCORT AQUA Nasal Spray regularly. Do not stop using RHINOCORT AQUA Nasal Spray or change your dose without talking to your healthcare provider, even if you are feeling better.\n", "\nTalk to your healthcare provider if your symptoms do not improve after taking RHINOCORT AQUA Nasal Spray for 2 weeks or if your symptoms get worse.\n", "\nAn adult should help a young child use this medicine.\n", "\nSee the Patient Instructions for Use at the end of this leaflet for complete information on how to use RHINOCORT AQUA Nasal Spray.\n" ], "text": "" }

What are the possible side effects of RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the possible side effects of RHINOCORT AQUA Nasal Spray?\n" }

RHINOCORT AQUA Nasal Spray may cause serious side effects including:

{ "type": "p", "children": [], "text": "\nRHINOCORT AQUA Nasal Spray may cause serious side effects including:\n" }

{ "type": "ul", "children": [ "\n\nhole in the cartilage inside the nose (nasal septal perforation). Tell your healthcare provider if you have a whistling sound from your nose when you breathe.\n\n\n\n", "\n\nslow wound healing. You should not use RHINOCORT AQUA Nasal Spray until your nose has healed if you have a sore in your nose, if you have had surgery on your nose, or if your nose has been injured.\n", "\n fungal infection in your nose.\n", "\nallergic reactions. Tell your healthcare provider or get medical help right away if you have:", " skin rash, redness or swelling", " severe itching", " swelling of the face, mouth and tongue\n\n\n", "\n\nimmune system problems that may increase your risk of infections. You are more likely to get infections if you take medicines that weaken your body’s ability to fight infections. Avoid contact with people who have contagious diseases such as chicken pox or measles while using RHINOCORT AQUA Nasal Spray. Symptoms of infection may include fever, pain, aches, chills, feeling tired, nausea and vomiting.\n\n\n\n", "\n\nadrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. Symptoms of adrenal insufficiency may include tiredness, weakness, nausea, vomiting and low blood pressure.\n\n\n\n", "\n\nslowed or delayed growth in children. A child’s growth should be checked regularly while using RHINOCORT AQUA Nasal Spray.\n", "\n\neye problems, such as glaucoma and cataracts. Tell your healthcare provider if you have a change in vision or have a history of increased intraocular pressure, glaucoma, and/or cataracts.\n" ], "text": "" }

Call your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.

{ "type": "p", "children": [], "text": "\nCall your healthcare provider or get medical help right away if you have symptoms of any of the serious side effects listed above.\n" }

The most common side effects of RHINOCORT AQUA Nasal Spray include:

{ "type": "p", "children": [], "text": "The most common side effects of RHINOCORT AQUA Nasal Spray include:" }

{ "type": "ul", "children": [ "\nnose bleeds\n", "\nsore throat\n", "\nbreathing difficulties such as wheezing, or chest tightening \n", "\ncough\n", "\nirritation of your nose\n" ], "text": "" }

Tell your healthcare provider if you have any side effect that bothers you or does not go away.

{ "type": "p", "children": [], "text": "Tell your healthcare provider if you have any side effect that bothers you or does not go away." }

These are not all of the possible side effects of RHINOCORT AQUA Nasal Spray. For more information, ask your healthcare provider or pharmacist.

{ "type": "p", "children": [], "text": "These are not all of the possible side effects of RHINOCORT AQUA Nasal Spray. For more information, ask your healthcare provider or pharmacist. " }

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

{ "type": "p", "children": [], "text": "Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch." }

You may report side effects to AstraZeneca at 1-800-236-9933.

{ "type": "p", "children": [], "text": " You may report side effects to AstraZeneca at 1-800-236-9933." }

What should I know about allergic rhinitis?

{ "type": "p", "children": [], "text": "\nWhat should I know about allergic rhinitis? \n" }

“Rhinitis” means inflammation of the lining of the nose. It is sometimes called “hay fever.” Allergic rhinitis can be caused by allergies to pollen, animal dander, house dust mite, and mold spores. If you have allergic rhinitis, your nose becomes stuffy, runny, and itchy. You may also sneeze a lot. You may have red, itchy, watery eyes; itchy throat; or blocked, itchy ears.

{ "type": "p", "children": [], "text": "“Rhinitis” means inflammation of the lining of the nose. It is sometimes called “hay fever.” Allergic rhinitis can be caused by allergies to pollen, animal dander, house dust mite, and mold spores. If you have allergic rhinitis, your nose becomes stuffy, runny, and itchy. You may also sneeze a lot. You may have red, itchy, watery eyes; itchy throat; or blocked, itchy ears." }

RHINOCORT AQUA Nasal Spray helps to relieve your nasal symptoms.

{ "type": "p", "children": [], "text": "RHINOCORT AQUA Nasal Spray helps to relieve your nasal symptoms. " }

If you also have itchy, watery eyes, you should tell your healthcare provider. He or she can prescribe additional medication to treat these symptoms.

{ "type": "p", "children": [], "text": "If you also have itchy, watery eyes, you should tell your healthcare provider. He or she can prescribe additional medication to treat these symptoms." }

How should I store RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nHow should I store RHINOCORT AQUA Nasal Spray?\n" }

{ "type": "ul", "children": [ "\nStore RHINOCORT AQUA Nasal Spray at 68°F to 77°F (20°C to 25°C).\n", "\nDo not freeze RHINOCORT AQUA Nasal Spray.\n", "\nProtect RHINOCORT AQUA Nasal Spray from light.\n", "\nDo not use RHINOCORT AQUA Nasal Spray after the labeled number of sprays have been used (does not include priming) or after the expiration date shown on the carton or bottle label.\n", "\nKeep the green protective cap on RHINOCORT AQUA Nasal Spray when not in use. (Please see Prior to Use on reverse side).\n", "\nKeep RHINOCORT AQUA Nasal Spray and all medications out of the reach of children.\n" ], "text": "" }

General Information about the safe and effective use of RHINOCORT AQUA Nasal Spray:

{ "type": "p", "children": [], "text": "\nGeneral Information about the safe and effective use of RHINOCORT AQUA Nasal Spray:\n" }

Do not use RHINOCORT AQUA Nasal Spray for a condition for which it was not prescribed. Do not give RHINOCORT AQUA Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them.

{ "type": "p", "children": [], "text": "Do not use RHINOCORT AQUA Nasal Spray for a condition for which it was not prescribed. Do not give RHINOCORT AQUA Nasal Spray to other people, even if they have the same symptoms that you have. It may harm them." }

This Patient Information leaflet summarizes the most important information about RHINOCORT AQUA Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about RHINOCORT AQUA Nasal Spray that is written for health professionals.

{ "type": "p", "children": [], "text": "This Patient Information leaflet summarizes the most important information about RHINOCORT AQUA Nasal Spray. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about RHINOCORT AQUA Nasal Spray that is written for health professionals. " }

For more information, go to www.astrazenca-us.com or call AstraZeneca at 1-800-236-9933.

{ "type": "p", "children": [], "text": "For more information, go to www.astrazenca-us.com or call AstraZeneca at 1-800-236-9933." }

What are the Ingredients of RHINOCORT AQUA Nasal Spray?

{ "type": "p", "children": [], "text": "\nWhat are the Ingredients of RHINOCORT AQUA Nasal Spray?\n" }

Active ingredient: budesonide

{ "type": "p", "children": [], "text": "Active ingredient: budesonide" }

Inactive ingredients:

{ "type": "p", "children": [], "text": "Inactive ingredients:" }

Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, purified water and hydrochloric acid.

{ "type": "p", "children": [], "text": "Microcrystalline cellulose and carboxymethyl cellulose sodium, dextrose anhydrous, polysorbate 80, disodium edetate, potassium sorbate, purified water and hydrochloric acid." }

Patient Instructions for Use

{ "type": "p", "children": [], "text": "\nPatient Instructions for Use\n" }

For use in your nose only. Do not spray in your eyes or mouth.

{ "type": "p", "children": [], "text": "For use in your nose only. Do not spray in your eyes or mouth. " }

Read the Patient Instructions for Use carefully before you start to use RHINOCORT AQUA Nasal Spray. If you have any questions, ask your healthcare provider.

{ "type": "p", "children": [], "text": "Read the Patient Instructions for Use carefully before you start to use RHINOCORT AQUA Nasal Spray. If you have any questions, ask your healthcare provider." }

Figure A

{ "type": "p", "children": [], "text": "Figure A" }

How to prime your RHINOCORT AQUA Nasal Spray

{ "type": "p", "children": [], "text": "\nHow to prime your RHINOCORT AQUA Nasal Spray \n" }

Before you use RHINOCORT AQUA Nasal Spray, the bottle must be primed. To prime RHINOCORT AQUA Nasal Spray:

{ "type": "p", "children": [], "text": "Before you use RHINOCORT AQUA Nasal Spray, the bottle must be primed. To prime RHINOCORT AQUA Nasal Spray:" }

1. Pull to remove the green protective cap off the nasal spray unit.

{ "type": "p", "children": [], "text": "\n1. Pull to remove the green protective cap off the nasal spray unit." }

2. Shake the bottle gently for a few seconds before each use.

{ "type": "p", "children": [], "text": "\n2.\tShake the bottle gently for a few seconds before each use.\n" }

3.Hold the bottle firmly, as shown in Figure B, with your index and middle finger on either side of the spray tip and your thumb underneath the bottle.

{ "type": "p", "children": [], "text": "\n3.Hold the bottle firmly, as shown in Figure B, with your index and middle finger on either side of the spray tip and your thumb underneath the bottle." }

Figure B

{ "type": "p", "children": [], "text": "Figure B" }

4. Activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb.

{ "type": "p", "children": [], "text": "\n4. Activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb." }

5. Before your first use of RHINOCORT AQUA Nasal Spray, shake the bottle gently. The pump must be primed by pressing down on the white collar 8 times. The pump is now ready to use. If used daily the pump does not need to be reprimed. If not used for 2 days in a row, reprime with 1 spray or until a fine spray appears. If not used for more than 14 days, rinse the spray tip of the pump using the cleaning steps listed at the end of this leaflet. After cleaning reprime with 2 sprays or until a fine spray appears.

{ "type": "p", "children": [], "text": "\n5.\tBefore your first use of RHINOCORT AQUA Nasal Spray, shake the bottle gently. The pump must be primed by pressing down on the white collar 8 times. The pump is now ready to use. If used daily the pump does not need to be reprimed. If not used for 2 days in a row, reprime with 1 spray or until a fine spray appears. If not used for more than 14 days, rinse the spray tip of the pump using the cleaning steps listed at the end of this leaflet. After cleaning reprime with 2 sprays or until a fine spray appears." }

Each bottle of RHINOCORT AQUA Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times after the bottle is primed.

{ "type": "p", "children": [], "text": "Each bottle of RHINOCORT AQUA Nasal Spray contains enough medicine for you to spray medicine from the bottle 120 times after the bottle is primed." }

You should not use the bottle of RHINOCORT AQUA Nasal Spray after 120 sprays. Additional sprays after 120 may not contain the right amount of medicine. You should keep track of the number of sprays you use from each bottle of RHINOCORT AQUA Nasal Spray and throw away any remaining medicine that may be left in the bottle. Refill your prescription monthly.

{ "type": "p", "children": [], "text": "\nYou should not use the bottle of RHINOCORT AQUA Nasal Spray after 120 sprays. Additional sprays after 120 may not contain the right amount of medicine. You should keep track of the number of sprays you use from each bottle of RHINOCORT AQUA Nasal Spray and throw away any remaining medicine that may be left in the bottle. Refill your prescription monthly." }

How to use your RHINOCORT AQUA Nasal Spray

{ "type": "p", "children": [], "text": "\nHow to use your RHINOCORT AQUA Nasal Spray\n" }

Follow these instructions for daily use of RHINOCORT AQUA Nasal Spray:

{ "type": "p", "children": [], "text": "Follow these instructions for daily use of RHINOCORT AQUA Nasal Spray:" }

1. Gently blow your nose to clear your nostrils, if necessary.

{ "type": "p", "children": [], "text": "\n1.\tGently blow your nose to clear your nostrils, if necessary." }

2. Shake the bottle gently for a few seconds and remove the green protective cap.

{ "type": "p", "children": [], "text": "\n2.\tShake the bottle gently for a few seconds and remove the green protective cap.\n" }

3. Hold the bottle firmly with your index and middle finger on either side of the spray tip and your thumb underneath the bottle (See Figure C).

{ "type": "p", "children": [], "text": "\n3.\tHold the bottle firmly with your index and middle finger on either side of the spray tip and your thumb underneath the bottle (See Figure C)." }

Figure C

{ "type": "p", "children": [], "text": "Figure C" }

4. Insert the spray tip into your nostril (the tip should not reach far into your nose). Close the other nostril with a finger and lean your head slightly forward so the spray will aim toward the back of your nose (See Figure D).

{ "type": "p", "children": [], "text": "\n4.\tInsert the spray tip into your nostril (the tip should not reach far into your nose). Close the other nostril with a finger and lean your head slightly forward so the spray will aim toward the back of your nose (See Figure D)." }

Figure D

{ "type": "p", "children": [], "text": "Figure D" }

5. For each spray, activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb. Breathe gently inward through the nostril.

{ "type": "p", "children": [], "text": "\n5.\tFor each spray, activate the pump by quickly and firmly pressing down on the white collar while holding the base of the bottle with your thumb. Breathe gently inward through the nostril." }

6. After spraying into your nostril, lean your head backward for a few seconds (Figure E).

{ "type": "p", "children": [], "text": "\n6.\tAfter spraying into your nostril, lean your head backward for a few seconds (Figure E)." }

Figure E

{ "type": "p", "children": [], "text": "Figure E" }

7. If a second spray is needed in the same nostril, repeat steps 3 through 6.

{ "type": "p", "children": [], "text": "\n7.\tIf a second spray is needed in the same nostril, repeat steps 3 through 6." }

8. Repeat steps 3 through 7 for your other nostril.

{ "type": "p", "children": [], "text": "\n8.\tRepeat steps 3 through 7 for your other nostril." }

9. Avoid blowing your nose for 15 minutes after you use RHINOCORT AQUA Nasal Spray.

{ "type": "p", "children": [], "text": "\n9.\tAvoid blowing your nose for 15 minutes after you use RHINOCORT AQUA Nasal Spray." }

10. Wipe the spray tip with a clean tissue (Figure F), and replace the green protective cap. Store the bottle in an upright position.

{ "type": "p", "children": [], "text": "\n10.\tWipe the spray tip with a clean tissue (Figure F), and replace the green protective cap. Store the bottle in an upright position." }

Figure F

{ "type": "p", "children": [], "text": "Figure F" }

How to clean your RHINOORT AQUA Nasal Spray

{ "type": "p", "children": [], "text": "\nHow to clean your RHINOORT AQUA Nasal Spray\n" }

Figure G

{ "type": "p", "children": [], "text": "Figure G" }

Rinse the green protective cap and the spray tip regularly. To do this:

{ "type": "p", "children": [], "text": "Rinse the green protective cap and the spray tip regularly. To do this:" }

1. Remove the green protective cap and lift off the spray tip (See Figure G).

{ "type": "p", "children": [], "text": "\n1.\tRemove the green protective cap and lift off the spray tip (See Figure G)." }

2. Wash only the green protective cap and the spray tip in warm water and rinse them in cold tap water.

{ "type": "p", "children": [], "text": "\n2.\tWash only the green protective cap and the spray tip in warm water and rinse them in cold tap water." }

3. Allow the green protective cap and the spray tip to air-dry completely before reassembling the nasal spray.

{ "type": "p", "children": [], "text": "\n3.\tAllow the green protective cap and the spray tip to air-dry completely before reassembling the nasal spray." }

4.If the spray tip becomes blocked, it can be cleared by repeating Steps 1 through 3. Do not unblock the nasal applicator with a pin or other sharp object.

{ "type": "p", "children": [], "text": "\n4.If the spray tip becomes blocked, it can be cleared by repeating Steps 1 through 3. Do not unblock the nasal applicator with a pin or other sharp object.\n" }

For additional information about RHINOCORT AQUA® Nasal Spray, please call the AstraZeneca Information Center, Monday through Friday, 8 am – 6 pm ET, excluding holidays at 1-800-236-9933.

{ "type": "p", "children": [], "text": "For additional information about RHINOCORT AQUA® Nasal Spray, please call the AstraZeneca Information Center, Monday through Friday, 8 am – 6 pm ET, excluding holidays at 1-800-236-9933. " }

All trademarks are the property of the AstraZeneca group of companies

{ "type": "p", "children": [], "text": "All trademarks are the property of the AstraZeneca group of companies" }

©AstraZeneca 2008, 2009, 2010

{ "type": "p", "children": [], "text": "©AstraZeneca 2008, 2009, 2010" }

Distributed by:

{ "type": "p", "children": [], "text": "Distributed by:" }

AstraZeneca LP, Wilmington, DE 19850

{ "type": "p", "children": [], "text": "AstraZeneca LP, Wilmington, DE 19850" }

Rev. 12/10

{ "type": "p", "children": [], "text": "Rev. 12/10" }