Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • 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 asthma or acute episodes: PULMICORT FLEXHALER should not be used for relief of acute symptoms.

Patients require immediate re-evaluation during rapidly deteriorating asthma.

(5.2) • Hypersensitivity reactions: Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.

Discontinue PULMICORT FLEXHALER 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: Risk of impaired adrenal function when transferring from oral steroids.

Taper patients slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER.

(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 PULMICORT FLEXHALER slowly.

(5.6) • Reduction in bone mineral density with long term administration.

Monitor patients with major risk factors for decreased bone mineral content.

(5.8) • Effects on growth: Monitor growth of pediatric patients.

(5.9) • Glaucoma and cataracts: Close monitoring is warranted.

(5.10) • Paradoxical bronchospasm: Discontinue PULMICORT FLEXHALER and institute alternative therapy if paradoxical bronchospasm occurs.

(5.11) • Eosinophilic conditions and Churg-Strauss: Be alert to eosinophilic conditions.

(5.12) 5.1 Local Effects 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.

5.2 Deterioration of Asthma or Acute Episodes 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 beta 2 -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 2 -agonist (e.g.

albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER.

5.3 Hypersensitivity Reactions Including Anaphylaxis 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) and 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) and Adverse Reactions, Post-marketing Experience (6.2) ].

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 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., 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.

5.5 Transferring Patients from Systemic Corticosteroid Therapy 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 [FEV 1 ] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids.

In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

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.

5.6 Hypercorticism and Adrenal Suppression 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.

5.7 Interactions with Strong Cytochrome P450 3A4 Inhibitors 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 [ee Drug Interactions (7.1), Clinical Pharmacology (12.3) ].

5.8 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 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.

5.9 Effect 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 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) ].

5.10 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.

5.11 Paradoxical Bronchospasm and Upper Airway Symptoms 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 2 – bronchodilator.

PULMICORT FLEXHALER should be discontinued immediately, and alternative therapy should be instituted.

5.12 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 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response ( 5.1 ) Hypersensitivity reactions including anaphylaxis: Discontinue ATROVENT HFA at once and consider alternative treatments ( 5.2 ) Paradoxical bronchospasm: Discontinue ATROVENT HFA and consider other treatments if paradoxical bronchospasm occurs ( 5.3 ) Ocular effects: Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if signs or symptoms of narrow-angle glaucoma develop ( 5.4 ) Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if signs or symptoms of urinary retention develop ( 5.5 ) 5.1 Use for Maintenance Treatment Only ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.

5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after the administration of ATROVENT HFA.

In clinical trials and postmarketing experience with ipratropium-containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported [ see Adverse Reactions (6.1 , 6.2) ].

If such a reaction occurs, therapy with ATROVENT HFA should be stopped at once and alternative treatment should be considered [ see Contraindications (4) ] .

5.3 Paradoxical Bronchospasm ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening.

If this occurs, treatment with ATROVENT HFA should be stopped and other treatments considered.

5.4 Ocular Effects ATROVENT HFA is an anticholinergic and its use may increase intraocular pressure.

This may result in precipitation or worsening of narrow-angle glaucoma.

Therefore, ATROVENT HFA should be used with caution in patients with narrow-angle glaucoma [ see Drug Interactions (7.1) ].

Patients should avoid spraying ATROVENT HFA into their eyes.

If a patient sprays ATROVENT HFA into their eyes, they may cause eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos or colored images in association with red eyes from conjunctival and corneal congestion.

Advise patients to consult their physician immediately if any of these symptoms develop while using ATROVENT HFA Inhalation Aerosol.

5.5 Urinary Retention ATROVENT HFA is an anticholinergic and may cause urinary retention.

Therefore, caution is advised when administering ATROVENT HFA Inhalation Aerosol to patients with prostatic hyperplasia, or bladder-neck obstruction [ see Drug Interactions (7.1) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Postural hypotension with or without syncope may occur.

( 5.1 ) • Risk of Intraoperative Floppy Iris Syndrome during cataract surgery.

( 5.2 ) • Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards.

( 5.3 ) 5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin tablets.

However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing.

As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength.

Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop.

Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.

5.2 Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha 1 blockers.

This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions.

The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

There does not appear to be a benefit of stopping alpha 1 blocker therapy prior to cataract surgery.

5.3 Prostate Cancer Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist.

Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin tablets for the treatment of BPH.

5.4 Priapism Alpha 1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation).

This condition can lead to permanent impotence if not promptly treated.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation.

Discontinue warfarin sodium and consider alternative anticoagulants if necessary.

( 5.2 ) Calciphylaxis: Fatal and serious cases have occurred.

Discontinue warfarin sodium and consider alternative anticoagulation therapy.

( 5.3 ) Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria.

( 5.4 ) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue warfarin sodium if such emboli occur.

( 5.5 ) Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death.

Warfarin sodium may be considered after platelet count has normalized.

( 5.6 ) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.

( 5.7 ) 5.1 Hemorrhage Warfarin sodium can cause major or fatal bleeding.

Bleeding is more likely to occur within the first month.

Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients.

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition.

However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.

Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

5.2 Tissue Necrosis Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which is an uncommon but serious risk (<0.1%).

Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy.

In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease.

Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective.

Discontinue warfarin sodium therapy if necrosis occurs.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Calciphylaxis Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.

When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate.

Consider alternative anticoagulation therapy.

5.4 Acute Kidney Injury In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6) ].

More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli.

Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization.

The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver.

Some cases have progressed to necrosis or death.

A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue warfarin sodium therapy if such phenomena are observed.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).

Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued.

In some patients, sequelae have included amputation of the involved area and/or death.

Treatment with warfarin sodium may be considered after the platelet count has normalized.

5.7 Use in Pregnant Women with Mechanical Heart Valves Warfarin sodium can cause fetal harm when administered to a pregnant woman.

While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism.

In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines.

Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

5.8 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of warfarin sodium therapy may be increased: Moderate to severe hepatic impairment Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) Use of an indwelling catheter Severe to moderate hypertension Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S.

Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients.

Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications.

As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.

Polycythemia vera Vasculitis Diabetes mellitus 5.9 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation.

Discontinue warfarin sodium and consider alternative anticoagulants if necessary.

( 5.2 ) Calciphylaxis: Fatal and serious cases have occurred.

Discontinue warfarin sodium and consider alternative anticoagulation therapy.

( 5.3 ) Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria.

( 5.4 ) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue warfarin sodium if such emboli occur.

( 5.5 ) Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death.

Warfarin sodium may be considered after platelet count has normalized.

( 5.6 ) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.

( 5.7 ) 5.1 Hemorrhage Warfarin sodium can cause major or fatal bleeding.

Bleeding is more likely to occur within the first month.

Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy.

Perform regular monitoring of INR in all treated patients.

Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition.

However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding.

Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy.

Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ].

Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ].

5.2 Tissue Necrosis Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which is an uncommon but serious risk (<0.1%).

Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy.

In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported.

Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease.

Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective.

Discontinue warfarin sodium therapy if necrosis occurs.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.3 Calciphylaxis Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.

When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate.

Consider alternative anticoagulation therapy.

5.4 Acute Kidney Injury In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6) ].

More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli.

Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization.

The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver.

Some cases have progressed to necrosis or death.

A distinct syndrome resulting from microemboli to the feet is known as “purple toes syndrome.” Discontinue warfarin sodium therapy if such phenomena are observed.

Consider alternative drugs if continued anticoagulation therapy is necessary.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS).

Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued.

In some patients, sequelae have included amputation of the involved area and/or death.

Treatment with warfarin sodium may be considered after the platelet count has normalized.

5.7 Use in Pregnant Women with Mechanical Heart Valves Warfarin sodium can cause fetal harm when administered to a pregnant woman.

While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism.

In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient’s medical situation, as well as the most current medical guidelines.

Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ].

5.8 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of warfarin sodium therapy may be increased: Moderate to severe hepatic impairment Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) Use of an indwelling catheter Severe to moderate hypertension Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S.

Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration.

Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients.

Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications.

As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits.

Polycythemia vera Vasculitis Diabetes mellitus 5.9 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency.

The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS LABA monotherapy increases the risk of serious asthma-related events.

( 5.1 ) Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms.

( 5.2 ) Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose.

( 5.3 ) Localized infections: Candida albicans infection of the mouth and throat may occur.

Monitor patients periodically for signs of adverse effects on the oral cavity.

After dosing, advise patients to rinse their mouth with water and spit out contents without swallowing.

( 5.4 ) Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

Use with caution in patients with these infections because of the potential for worsening of these infections.

( 5.5 ) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids.

Taper patients slowly from systemic corticosteroids if transferring to DULERA.

( 5.6 ) Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, discontinue DULERA slowly.

( 5.7 ) Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects.

Exercise caution when used with DULERA.

( 5.8 ) Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs.

( 5.9 ) Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation.

( 5.11 ) Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content.

( 5.12 ) Effects on growth: Monitor growth of pediatric patients.

( 5.13 ) Glaucoma and cataracts: Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term.

( 5.14 ) Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis.

( 5.15 ) Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia.

( 5.16 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, and Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART) ] .

Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients.

These findings are considered a class effect of LABA monotherapy.

When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone [see Serious Asthma-Related Events with ICS/LABA ] .

Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma.

Three trials included adult and adolescent patients aged ≥12 years: one trial compared mometasone furoate/formoterol (DULERA) to mometasone furoate [see Clinical Studies (14.1) ] ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared budesonide/formoterol to budesonide.

The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder.

The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death).

A blinded adjudication committee determined whether events were asthma-related.

The three adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk of 2.7.

Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone.

A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1).

These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS.

Table 1: Meta-Analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS/LABA (N=17,537) Randomized patients who had taken at least 1 dose of study drug.

Planned treatment used for analysis.

ICS (N=17,552) ICS/LABA vs.

ICS Hazard ratio (95% CI) Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.

ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist.

Serious asthma-related event Number of patients with events that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later.

Patients can have one or more events, but only the first event was counted for analysis.

A single, blinded, independent adjudication committee determined whether events were asthma-related.

116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24 hour stay) 115 105 The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder).

In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and 21/3101 (0.7%) patients randomized to ICS experienced a serious asthma-related event.

There were no asthma-related deaths or intubations.

ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27).

Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled U.S.

trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs.

3/13,179 in patients treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]).

Use of background ICS was not required in SMART.

The increased risk of asthma-related death is considered a class effect of LABA monotherapy.

Formoterol Monotherapy Studies Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo.

The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups.

5.2 Deterioration of Disease and Acute Episodes DULERA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma.

DULERA has not been studied in patients with acutely deteriorating asthma.

The initiation of DULERA in this setting is not appropriate.

Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma.

In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids.

Patients should not use more than 2 inhalations twice daily (morning and evening) of DULERA.

DULERA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm.

An inhaled, short-acting beta 2 -agonist, not DULERA, should be used to relieve acute symptoms such as shortness of breath.

When beginning treatment with DULERA, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

5.3 Excessive Use of DULERA and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -adrenergic agents, DULERA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta 2 -agonists, as an overdose may result.

Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using DULERA should not use an additional long-acting beta 2 -agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma.

5.4 Local Effects In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with DULERA.

If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with DULERA therapy, but at times therapy with DULERA may need to be interrupted.

To reduce the risk of oropharyngeal candidiasis, after dosing with DULERA, advise patients to rinse their mouth with water and spit out the contents without swallowing.

5.5 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox 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 who are not 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 chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) 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 chickenpox develops, treatment with antiviral agents may be considered.

DULERA 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.

5.6 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to DULERA 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 DULERA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.

During periods of stress or 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 severe asthma attack.

Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to DULERA.

Lung function (FEV 1 or PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic 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 DULERA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

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

5.7 Hypercorticism and Adrenal Suppression Mometasone furoate, a component of DULERA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of DULERA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with DULERA 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 mometasone furoate is administered at higher than recommended doses over prolonged periods of time.

If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of DULERA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

5.9 Paradoxical Bronchospasm and Upper Airway Symptoms DULERA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening.

If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator.

DULERA should be discontinued immediately and alternative therapy instituted.

5.10 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of DULERA, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.

5.11 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia.

Therefore, DULERA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms.

Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug may need to be discontinued.

In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.

The clinical significance of these findings is unknown.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.12 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of DULERA.

The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, 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.

In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV 1 85%–88% predicted), treatment with mometasone furoate dry powder inhaler (DPI) 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo.

The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate group compared to 0.002 (0.25%) for the placebo group.

In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV 1 82%–83% predicted), treatment with mometasone furoate 400 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo.

The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group compared to -0.006 (-0.43%) for the placebo group.

5.13 Effect on Growth Orally inhaled corticosteroids, including DULERA, may cause a reduction in growth velocity when administered to pediatric patients.

Monitor the growth of pediatric patients receiving DULERA routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4) ] .

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate, a component of DULERA.

Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term [see Adverse Reactions (6) ] .

5.15 Coexisting Conditions DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines.

Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta 2 -agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.

The decrease in serum potassium is usually transient, not requiring supplementation.

Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with DULERA at recommended doses.