Author: druginteractionchecker_lgaiz4

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Contamination of Tip and Solution.

To prevent contaminating the dropper tip and solution, do not touch the eyelids or surrounding areas with the dropper tip of the bottle.

(5.1) 5.1 CONTAMINATION OF TIP AND SOLUTION As with any eye drop, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle to prevent contaminating the tip and solution.

Keep bottle tightly closed when not in use.

5.2 CONTACT LENS USE Patients should not wear a contact lens if their eye is red.

The preservative in PAZEO solution, benzalkonium chloride, may be absorbed by soft contact lenses.

Patients who wear soft contact lenses and whose eyes are not red, should be instructed to wait at least five minutes after instilling PAZEO before they insert their contact lenses.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Gastric Malignancy :In adults, symptomatic response does not preclude the presence of gastric malignancy.

Consider additional follow-up and diagnostic testing.

(5.1) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients.

(5.2) Clostridium difficile-Associated Diarrhea : PPI therapy may be associated with increased risk (5.3) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.

(5.4) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

(5.5 ) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium and refer to specialist for evaluation.

(5.6) Interaction with Clopidogrel: Avoid concomitant use of esomeprazole magnesium.

(5.7) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin.

(5.8) Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged treatment with PPIs.

(5.9) Interaction with St.

John’s Wort or Rifampin: Avoid concomitant use of esomeprazole magnesium.

( 5.10 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increased chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors, temporarily stop esomeprazole magnesium at least 14 days before assessing CgA levels.

( 5.11 , 12.2 ) Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity.

With high dose methotrexate administration, consider temporary withdrawal of esomeprazole magnesium.

( 5.12 , 7 ) Fundic Gland Polyps: Risk increases with long-term use, especially beyond one year.

Use the shortest duration of therapy.

(5.13) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with esomeprazole magnesium does not preclude the presence of gastric malignancy.

Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI.

In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy.

Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to nonspecific symptoms of decreased renal function (e.g., malaise, nausea, anorexia).

In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).

Discontinue esomeprazole magnesium and evaluate patients with suspected acute TIN [see Contraindications ( 4 )].

5.3 Clostridium difficile – Associated Diarrhea Published observational studies suggest that PPI therapy like esomeprazole magnesium may be associated with an increased risk of Clostridium difficile-associated diarrhea, especially in hospitalized patients.

This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions ( 6.2 )].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents.

For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with esomeprazole magnesium, refer to Warnings and Precautions section of the corresponding prescribing information.

5.4 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine.

The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer).

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2 ) and Adverse Reactions (6.2) ].

5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions ( 6.2 )].

Discontinue esomeprazole magnesium at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole.

These events have occurred as both new onset and an exacerbation of existing autoimmune disease.

The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly.

Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs.

PPI associated SLE is usually milder than non-drug induced SLE.

Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly.

The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated.

If signs or symptoms consistent with CLE or SLE are noted in patients receiving esomeprazole magnesium, discontinue the drug and refer the patient to the appropriate specialist for evaluation.

Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks.

Serological testing (e.g.

ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Interaction with Clopidogrel Avoid concomitant use of esomeprazole magnesium with clopidogrel.

Clopidogrel is a prodrug.

Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite.

The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity.

Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel.

When using esomeprazole magnesium consider alternative anti-platelet therapy [see Drug Interactions ( 7 )].

5.8 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria.

Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature.

This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

5.9 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy.

Serious adverse events include tetany, arrhythmias, and seizures.

Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.

In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions ( 6.2 )] Consider monitoring magnesium and calcium levels prior to initiation of esomeprazole and magnesium and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism).

Supplement with magnesium and/or calcium, as necessary.

If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.10 Interaction with St.

John’s Wort or Rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St.

John’s Wort or rifampin) can substantially decrease esomeprazole concentrations.

[see Drug Interactions (7 )].

Avoid concomitant use of esomeprazole magnesium with St.

John’s Wort, or rifampin.

5.11 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors.

Healthcare providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high.

If serial tests are performed (e.g.

for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Clinical Pharmacology (12.2 )].

5.12 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities.

In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions ( 7 )].

5.13 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.

Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy.

Use the shortest duration of PPI therapy appropriate to the condition being treated.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity.

Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop.

( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs.

Monitor blood pressure.

( 5.4 , 7 ) Heart Failure and Edema : Avoid use of celecoxib capsules in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Avoid use of celecoxib capsules in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.

( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs.

( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : Celecoxib is contraindicated in patients with aspirin-sensitive asthma.

Monitor patients with preexisting asthma (without aspirin sensitivity).

( 5.8 ) Serious Skin Reactions : Discontinue celecoxib capsules at first appearance of skin rash or other signs of hypersensitivity.

( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically.

( 5.10 ) Fetal Toxicity : Limit use of NSAIDs, including celecoxib capsules, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction.

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus.

( 5.11 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia.

( 5.12 , 7 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several cyclooxygenase-2 (COX-2) selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

In the APC (Adenoma Prevention with Celecoxib) trial, there was about a threefold increased risk of the composite endpoint of cardiovascular death, MI, or stroke for the celecoxib 400 mg twice daily and celecoxib 200 mg twice daily treatment arms compared to placebo.

The increases in both celecoxib dose groups versus placebo-treated patients were mainly due to an increased incidence of myocardial infarction [see Clinical Studies (14.7) ] .

A randomized controlled trial entitled the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs.

Ibuprofen Or Naproxen (PRECISION) was conducted to assess the relative cardiovascular thrombotic risk of a COX-2 inhibitor, celecoxib, compared to the non-selective NSAIDs naproxen and ibuprofen.

Celecoxib 100 mg twice daily was non-inferior to naproxen 375 to 500 mg twice daily and ibuprofen 600 to 800 mg three times daily for the composite endpoint of the Antiplatelet Trialists’ Collaboration (APTC), which consists of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction, and non-fatal stroke [see Clinical Studies (14.6) ] .

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as celecoxib, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ] .

Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ] .

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of celecoxib in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If celecoxib is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal.

These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with celecoxib.

Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic.

Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year.

However, even short-term NSAID therapy is not without risk.

Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, antiplatelet drugs (such as aspirin), anticoagulants; or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status.

Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients.

Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Complicated and symptomatic ulcer rates were 0.78% at nine months for all patients in the CLASS trial, and 2.19% for the subgroup on low-dose ASA.

Patients 65 years of age and older had an incidence of 1.40% at nine months, 3.06% when also taking ASA [see Clinical Studies (14.7) ] .

Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration.

Avoid administration of more than one NSAID at a time.

Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding.

For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.

Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue celecoxib until a serious GI adverse event is ruled out.

In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ] .

5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials.

In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.

Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including celecoxib.

In controlled clinical trials of celecoxib, the incidence of borderline elevations (greater than or equal to 1.2 times and less than 3 times the upper limit of normal) of liver associated enzymes was 6% for celecoxib and 5% for placebo, and approximately 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of ALT and AST.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).

If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash), discontinue celecoxib capsules immediately, and perform a clinical evaluation of the patient.

5.4 Hypertension NSAIDs, including celecoxib, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events.

Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7) ] .

See Clinical Studies ( 14.

6 , 14.7 ) for additional blood pressure data for celecoxib.

Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.

Use of celecoxib may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7) ] .

In the CLASS study [ see Clinical Studies (14.7) ] , the Kaplan-Meier cumulative rates at 9 months of peripheral edema in patients on celecoxib capsules 400 mg twice daily (4-fold and 2-fold the recommended OA and RA doses, respectively), ibuprofen 800 mg three times daily and diclofenac 75 mg twice daily were 4.5%, 6.9% and 4.7%, respectively.

Avoid the use of celecoxib capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If celecoxib capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.

Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion.

In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation.

Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics, ACE inhibitors or the ARBs, and the elderly.

Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

No information is available from controlled clinical studies regarding the use of celecoxib in patients with advanced renal disease.

The renal effects of celecoxib may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating celecoxib.

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of celecoxib [see Drug Interactions (7) ] .

Avoid the use of celecoxib in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function.

If celecoxib capsules are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment.

In patients with normal renal function, these effects have been attributed to a hyporeninemic- hypoaldosteronism state.

5.7 Anaphylactic Reactions Celecoxib has been associated with anaphylactic reactions in patients with and without known hypersensitivity to celecoxib and in patients with aspirin sensitive asthma.

Celecoxib is a sulfonamide and both NSAIDs and sulfonamides may cause allergic type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people [see Contraindications (4) and Warnings and Precautions (5.8) ] .

Seek emergency help if any anaphylactic reaction occurs.

5.8 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs.

Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, celecoxib is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ] .

When celecoxib capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.9 Serious Skin Reactions Serious skin reactions have occurred following treatment with celecoxib, including erythema multiforme, exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP).

These serious events may occur without warning and can be fatal.

Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of celecoxib capsules at the first appearance of skin rash or any other sign of hypersensitivity.

Celecoxib is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ] .

5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as celecoxib.

Some of these events have been fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.

Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.

Sometimes symptoms of DRESS may resemble an acute viral infection.

Eosinophilia is often present.

Because this disorder is variable in its presentation, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

If such signs or symptoms are present, discontinue celecoxib and evaluate the patient immediately.

5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including celecoxib, in pregnant women at about 30 weeks gestation and later.

NSAIDs, including celecoxib, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including celecoxib, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation.

Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation.

In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit celecoxib use to the lowest effective dose and shortest duration possible.

Consider ultrasound monitoring of amniotic fluid if celecoxib treatment extends beyond 48 hours.

Discontinue celecoxib if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations ( 8.1 )] .

5.12 Hematological Toxicity Anemia has occurred in NSAID-treated patients.

This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.

If a patient treated with celecoxib has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

In controlled clinical trials the incidence of anemia was 0.6% with celecoxib and 0.4% with placebo.

Patients on long-term treatment with celecoxib should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

NSAIDs, including celecoxib, may increase the risk of bleeding events.

Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet drugs (e.g., aspirin), SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk.

Monitor these patients for signs of bleeding [see Drug Interactions (7) ] .

5.13 Masking of Inflammation and Fever The pharmacological activity of celecoxib in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.14 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions ( 5.2 , 5.3 , 5.6 )] .

In controlled clinical trials, elevated BUN occurred more frequently in patients receiving celecoxib compared with patients on placebo.

This laboratory abnormality was also seen in patients who received comparator NSAIDs in these studies.

The clinical significance of this abnormality has not been established.

5.15 Disseminated Intravascular Coagulation (DIC) Because of the risk of disseminated intravascular coagulation with use of celecoxib in pediatric patients with systemic onset JRA, monitor patients for signs and symptoms of abnormal clotting or bleeding, and inform patients and their caregivers to report symptoms as soon as possible.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Angioedema and hypersensitivity reactions: Such reactions, including angioedema, infrequently life threatening, have been reported.

Instruct patients to discontinue CHANTIX and immediately seek medical care if symptoms occur.

( 5.2 and 6.2 ) Serious skin reactions: Rare, potentially life-threatening skin reactions have been reported.

Instruct patients to discontinue CHANTIX and contact a healthcare provider immediately at first appearance of skin rash with mucosal lesions.

( 5.3 and 6.2 ) Cardiovascular events: In a trial of patients with stable cardiovascular disease (CVD) certain cardiovascular events were reported more frequently in patients treated with CHANTIX.

Patients with CVD should be instructed to notify their health care providers of new or worsening cardiovascular symptoms and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction.

( 5.4 and 6.1 ) Accidental injury: Accidental injuries (e.g., traffic accidents) have been reported.

Instruct patients to use caution driving or operating machinery until they know how CHANTIX may affect them.

( 5.5 ) Nausea: Nausea is the most common adverse reaction (up to 30% incidence rate).

Dose reduction may be helpful.

( 5.6 ) 5.1 Neuropsychiatric Symptoms and Suicidality Serious neuropsychiatric symptoms have been reported in patients being treated with CHANTIX [see Boxed Warning and Adverse Reactions (6.2) ] .

These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide.

Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking.

Depressed mood may be a symptom of nicotine withdrawal.

Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication.

However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke.

When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.

These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses.

All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness.

Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established.

Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior.

In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

The risks of CHANTIX should be weighed against the benefits of its use.

CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.

The health benefits of quitting smoking are immediate and substantial.

5.2 Angioedema and Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX [see Adverse Reactions (6.2) , and Patient Counseling Information (17.10) ] .

Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx).

There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise.

Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.

5.3 Serious Skin Reactions There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX [see Adverse Reactions (6.2) ].

As these skin reactions can be life-threatening, instruct patients to stop taking CHANTIX and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.

5.4 Cardiovascular Events In a controlled clinical trial of CHANTIX administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, certain cardiovascular events were reported more frequently in patients treated with CHANTIX than in patients treated with placebo [see Clinical Trials Experience (6.1) ] .

These included treatment-emergent events (on-treatment or 30 days after treatment) of angina pectoris (13 patients in the varenicline arm vs.

7 in the placebo arm), and the serious cardiovascular events of nonfatal MI (4 vs.

1) and nonfatal stroke (2 vs.

0).

During non-treatment follow up to 52 weeks, serious cardiovascular events included nonfatal myocardial infarction (3 vs.

2), need for coronary revascularization (7 vs.

2), hospitalization for angina pectoris (6 vs.

4), transient ischemic attack (1 vs.

0), new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (5 vs.

2).

Serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by an independent blinded committee.

CHANTIX was not studied in patients with unstable cardiovascular disease or cardiovascular events occurring within two months before screening.

Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease.

The risks of CHANTIX should be weighed against the benefits of its use in smokers with cardiovascular disease.

Smoking is an independent and major risk factor for cardiovascular disease.

CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.

5.5 Accidental Injury There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX.

In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery.

Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how CHANTIX may affect them .

5.6 Nausea Nausea was the most common adverse reaction reported with CHANTIX treatment.

Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months.

The incidence of nausea was dose-dependent.

Initial dose-titration was beneficial in reducing the occurrence of nausea.

For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen.

In patients taking CHANTIX 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo.

Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea.

For patients with intolerable nausea, a dose reduction should be considered.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Anaphylactic reactions: Serious and occasionally fatal anaphylactic reactions have been reported in patients on penicillin therapy.

Serious anaphylactic reactions require immediate emergency treatment with supportive measures.

( 5.1 ) Clostridium difficile -associated diarrhea (ranging from mild diarrhea to fatal colitis): Evaluate if diarrhea occurs.

( 5.2 ) 5.1 Anaphylactic Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including amoxicillin.

Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins.

These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Before initiating therapy with AMOXICILLIN, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

If an allergic reaction occurs, AMOXICILLIN should be discontinued and appropriate therapy instituted.

5.2 Clostridium difficile Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AMOXICILLIN, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.

difficile .

C.

difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin-producing strains of C.

difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial use.

Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C.

difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

difficile , and surgical evaluation should be instituted as clinically indicated.

5.3 Development of Drug-Resistant Bacteria Prescribing AMOXICILLIN in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.4 Use in Patients With Mononucleosis A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash.

Thus amoxicillin should not be administered to patients with mononucleosis.

5.5 Phenylketonurics Amoxicillin chewable tablets contain aspartame which contains phenylalanine.

Each 200 mg chewable tablet contains 1.82 mg phenylalanine; each 400 mg chewable tablet contains 3.64 mg phenylalanine.

The oral suspensions of Amoxicillin do not contain phenylalanine and can be used by phenylketonurics.

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.