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<code code="43685-7" codeSystem="2.16.840.1.113883.6.1" displayName="WARNINGS AND PRECAUTIONS SECTION"/>
<title>5 WARNINGS AND PRECAUTIONS</title>
<effectiveTime value="20161025"/>
<excerpt>
<highlight>
<text>
<list listType="unordered">
<item>
<caption>•</caption>
<content styleCode="underline">Localized Infections:</content> 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 (<linkHtml href="#williamsonbk1261426025710">5.1</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Deterioration of Asthma or Acute Episodes:</content> PULMICORT FLEXHALER should not be used for relief of acute symptoms. Patients require immediate re-evaluation during rapidly deteriorating asthma (<linkHtml href="#ID_0ca59161-9284-48fb-845c-4846df38293c">5.2</linkHtml>) </item>
<item>
<caption>•</caption>
<content styleCode="underline">Hypersensitivity Reactions:</content> Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER. Discontinue PULMICORT FLEXHALER if such reactions occur (<linkHtml href="#williamsonbk1261426049273">5.3</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Immunosuppression:</content> 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 (<linkHtml href="#williamsonbk1261426063351">5.4</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Transferring Patients from Systemic Corticosteroid Therapy:</content> Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER (<linkHtml href="#williamsonbk1261593381742">5.5</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Hypercorticism and Adrenal Suppression:</content> May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, reduce PULMICORT FLEXHALER slowly (<linkHtml href="#williamsonbk1261426100257">5.6</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Reduction in Bone Mineral Density with Long term Administration:</content> Monitor patients with major risk factors for decreased bone mineral content (<linkHtml href="#williamsonbk1261426110382">5.8</linkHtml>)</item>
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<caption>•</caption>
<content styleCode="underline">Effects on Growth:</content> Monitor growth of pediatric patients (<linkHtml href="#williamsonbk1261426122289">5.9</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Glaucoma and Cataracts:</content> Close monitoring is warranted (<linkHtml href="#williamsonbk1261426139023">5.10</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Paradoxical Bronchospasm:</content> Discontinue PULMICORT FLEXHALER and institute alternative therapy if paradoxical bronchospasm occurs (<linkHtml href="#ID_59fb7df8-ffce-41ff-ae1e-016f52fbfbb4">5.11</linkHtml>)</item>
<item>
<caption>•</caption>
<content styleCode="underline">Eosinophilic Conditions and Churg-Strauss Syndrome:</content> Be alert to eosinophilic conditions (<linkHtml href="#williamsonbk1261426157679">5.12</linkHtml>)</item>
</list>
</text>
</highlight>
</excerpt>
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<title>5.1 Local Effects</title>
<text>
<paragraph>In clinical studies, the development of localized infections of the mouth and pharynx with <content styleCode="italics">Candida albicans</content> 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.</paragraph>
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<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.2 Deterioration of Asthma or Acute Episodes</title>
<text>
<paragraph>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.</paragraph>
<paragraph>An inhaled short acting beta<sub>2</sub>-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 beta<sub>2</sub>-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER.</paragraph>
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<effectiveTime value="20161025"/>
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<title>5.3 Hypersensitivity Reactions Including Anaphylaxis</title>
<text>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#williamsonbk1261578006898">Contraindications (4)</linkHtml>, <linkHtml href="#williamsonbk1261593016929">Adverse Reactions (6)</linkHtml>]</content>.</paragraph>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#williamsonbk1261578006898">Contraindications (4)</linkHtml>, <linkHtml href="#williamsonbk1261582265945">Adverse Reactions (6.2)</linkHtml>]</content>.</paragraph>
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<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261426063351">
<id root="71cf8591-6ce9-41fd-bf61-0459f20ef684"/>
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<title>5.4 Immunosuppression</title>
<text>
<paragraph>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.</paragraph>
<paragraph>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., beta<sub>2</sub>-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. </paragraph>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261593381742">
<id root="000c83c1-892f-44b4-9c45-ca411cee663c"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.5 Transferring Patients from Systemic Corticosteroid Therapy</title>
<text>
<paragraph>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. </paragraph>
<paragraph>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.</paragraph>
<paragraph>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. </paragraph>
<paragraph>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. </paragraph>
<paragraph>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 [FEV<sub>1</sub>] 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. </paragraph>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261426100257">
<id root="77ea55c7-cfd4-42d8-9d08-34ca13a00f0c"/>
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<title>5.6 Hypercorticism and Adrenal Suppression</title>
<text>
<paragraph>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. </paragraph>
<paragraph>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. </paragraph>
<paragraph>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.</paragraph>
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<effectiveTime value="20100710"/>
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<section ID="williamsonbk1261585227148">
<id root="d836b0b3-0df6-4cad-bfe9-02c4919d6298"/>
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<title>5.7 Interactions with Strong Cytochrome P450 3A4 Inhibitors</title>
<text>
<paragraph>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 <content styleCode="italics">[see <linkHtml href="#williamsonbk1261585257320">Drug Interactions (7.1)</linkHtml>, <linkHtml href="#nelsonjk1279208948541">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph>
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<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261426110382">
<id root="afb33b64-004c-4975-8d3c-775a459e23e9"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.8 Reduction in Bone Mineral Density</title>
<text>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261426122289">
<id root="17cc7b2c-bebe-4d7b-80c4-412d5b63d445"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.9 Effects on Growth</title>
<text>
<paragraph>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 <content styleCode="italics">[see </content>
<content styleCode="italics">
<linkHtml href="#nelsonjk1279208974307">Dosage and Administration (2.1)</linkHtml>
</content>
<content styleCode="italics">, <linkHtml href="#nelsonjk1279208993073">Use in Specific Populations (8.4)</linkHtml>]</content>.</paragraph>
</text>
<effectiveTime value="20161025"/>
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<component>
<section ID="williamsonbk1261426139023">
<id root="8ab9beeb-a7dc-48e8-9a0a-c721ca9b69d5"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.10 Glaucoma and Cataracts</title>
<text>
<paragraph>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.</paragraph>
</text>
<effectiveTime value="20100710"/>
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<section ID="ID_59fb7df8-ffce-41ff-ae1e-016f52fbfbb4">
<id root="3550905a-5caf-4215-9e53-e9a306f49983"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>5.11 Paradoxical Bronchospasm and Upper Airway Symptoms</title>
<text>
<paragraph>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 beta<sub>2</sub>-bronchodilator. PULMICORT FLEXHALER should be discontinued immediately, and alternative therapy should be instituted.</paragraph>
</text>
<effectiveTime value="20161025"/>
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<section ID="williamsonbk1261426157679">
<id root="ce08a276-8dd3-430b-9a91-7c5dd03a010f"/>
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<title>5.12 Eosinophilic Conditions and Churg-Strauss Syndrome</title>
<text>
<paragraph>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.</paragraph>
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