What Is Budesonide inhalation Inhalant Used For?

Budesonide inhalation suspension is an inhaled corticosteroid indicated for: • Maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age (1)

Limitations of Use: Not indicated for the relief of acute bronchospasm (1) 1.1 Maintenance Treatment of Asthma

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: • Budesonide inhalation suspension is NOT indicated for the relief of acute bronchospasm.

• Primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required. (4)

• Hypersensitivity to any of the ingredients in budesonide inhalation suspension (4) The use of budesonide inhalation suspension is contraindicated in the following conditions: • 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 [see

Warnings and Precautions (5.3), Description (11),Adverse Reactions(6.2)

].

Most common adverse reactions (incidence ≥3%) are respiratory infection, rhinitis, coughing, otitis media, viral infection, moniliasis, gastroenteritis, vomiting, diarrhea, abdominal pain, ear infection, epistaxis, conjunctivitis, rash (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd 1-866-604-3268 or FDA at 1-800-FDA-1088 or FDA or www.fda.gov/medwatch. Systemic and inhaled corticosteroid use may result in the following: • Candida albicans

Infection [see Warnings and Precautions (5.1)]

• Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.3)]

• Immunosuppression [see Warnings and Precautions (5.4)]

• Hypercorticism and Adrenal Suppression [

see Warnings and Precautions

(5.6)]

• Reduction in Bone Mineral Density [

see Warnings and Precautions

(5.7)]

• Growth Effects in Pediatric Patients [

see Warnings and Precautions

(5.8), Use in Specific Populations (8.4)]

• Glaucoma, Increased Intraocular Pressure and Cataracts [

see Warnings and Precautions

(5.9)]

• Eosinophilic Conditions and Churg-Strauss Syndrome [

see Warnings and Precautions

(5.11)] 6.1 Clinical Trials Experience

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.

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

Adverse Events

Vehicle Placebo (n=227) %

BUDESONIDE INHALATION SUSPENSION Total Daily Dose

0.25 mg (n=178) %

0.5 mg (n=223) %

1 mg (n=317) %

Respiratory System Disorder

Respiratory Infection

36

34

35

38

Rhinitis

9

7

11

12

Coughing

5

5

9

8

Resistance Mechanism Disorders

Otitis Media

11

12

11

9

Viral Infection

3

4

5

3

Moniliasis

2

4

3

4

Gastrointestinal System Disorders

Gastroenteritis

4

5

5

5

Vomiting

3

2

4

4

Diarrhea

2

4

4

2

Abdominal Pain

2

3

2

3

Hearing and Vestibular Disorders

Ear Infection

4

2

4

5

Platelet, Bleeding and Clotting Disorders

Epistaxis

1

2

4

3

Vision Disorders

Conjunctivitis

2

<1

4

2

Skin and Appendages Disorders

Rash

3

<1

4

2

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. 6.2 Post-marketing Experience

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), 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), Use in Specific Populations (8.4)

].

• Localized Infections: Candida albicans

infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.1)

• Deterioration of Disease and Acute Asthma Episodes

: Do not use for the relief of acute bronchospasm. (5.2)

• Hypersensitivity Reactions: 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 (5.3)

• Immunosuppression

: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. (5.4)

• Transferring Patients From Systemic Corticosteroids Therapy

: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to budesonide inhalation suspension (5.5)

• Hypercorticism and Adrenal Suppression

: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, reduce budesonide inhalation suspension slowly. (5.6)

• Reduction in Bone Mineral Density with Long-Term Administration: • Monitor patients with major risk factors for decreased bone mineral content. (5.7)

• Effects on Growth

: Monitor growth of pediatric patients. (5.8)

• Glaucoma and Cataracts

: Close monitoring is warranted. (5.9)

• Paradoxical Bronchospasm

: Discontinue budesonide inhalation suspension and institute alternative therapy if paradoxical bronchospasm occurs. (5.10)

• Eosinophilic Conditions and Churg-Strauss Syndrome

: Be alert to eosinophilic conditions. (5.11) 5.1 Local Effects

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. 5.2 Deterioration of Disease and Acute Asthma Episodes

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. 5.3 Hypersensitivity Reactions Including Anaphylaxis

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)

]. 5.4 Immunosuppression

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, 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. 5.5 Transferring Patients from Systemic Corticosteroid Therapy

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 (FEV1 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. 5.6 Hypercorticism and Adrenal Suppression

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. 5.7 Reduction in Bone Mineral Density

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. 5.8 Effects on Growth

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)

]. 5.9 Glaucoma and Cataracts

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. 5.10 Paradoxical Bronchospasm and Upper Airway Symptoms

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. 5.11 Eosinophilic Conditions and Churg-Strauss Syndrome

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. 5.12 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

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),

Clinical Pharmacology

(12.3)].

Recommended dosing based on previous therapy (2). Start with the lowest recommended dose: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily • 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 dailydose should be increased and/or administered as a divided dose. Once asthma stability is achieved, titrate the dose downwards. • For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices). Not for injection. (2.2) The recommended starting dose and highest recommended dose of budesonide inhalation suspension, based on prior asthma therapy, are listed in the following table. Previous Therapy Recommended Starting Dose Highest Recommended Dose Bronchodilators alone 0.5 mg total daily dose administered either once daily or twice daily in divided doses 0.5 mg total daily dose Inhaled Corticosteroids 0.5 mg total daily dose administered either once daily or twice daily in divided doses 1 mg total daily dose Oral Corticosteroids 1 mg total daily dose administered either as 0.5 mg twice daily or 1 mg once daily 1 mg total daily dose 2.1 Dosing Recommendations Dosing recommendations based on previous therapy are as follows: • Bronchodilators alone: 0.5 mg once daily or 0.25 mg twice daily • Inhaled corticosteroids: 0.5 mg once daily or 0.25 mg twice daily up to 0.5 mg twice daily • Oral corticosteroids: 0.5 mg twice daily or 1 mg once daily 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. 2.2 Directions for Use 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 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.

Inhalation suspension: 0.25 mg/2mL, 0.5 mg/2mL, 1 mg/2mL (3) Budesonide inhalation suspension is available in three strengths, each containing 2 mL: 0.25 mg/2 mL, 0.5 mg/2 mL, and 1 mg/2 mL. Budesonide inhalation suspension is supplied in sealed aluminum foil envelopes containing one plastic strip of either one single-dose ampule or five single-dose ampules together with patient instructions for use. There are 30 ampules in a carton. Each single-dose ampule contains 2 mL of sterile liquid suspension.

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), Clinical Pharmacology (12.3)].

• Strong Cytochrome P450 3A4 Inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (5.12, 7.1). 7.1 Inhibitors of Cytochrome P4503A4 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), Clinical Pharmacology (12.3) ].