FDA label bec41dcc-d3ff-9403-e053-2995a90a647c

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 Interstitial Nephritis : Observed in patients taking PPIs. (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) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue esomeprazole magnesium and refer to specialist for evaluation. ( 5.5 ) Interaction with Clopidogrel : Avoid concomitant use of esomeprazole magnesium. ( 5.6 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) Hypomagnesemia : Reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interaction with St. John’s Wort or Rifampin : Avoid concomitant use of esomeprazole magnesium. ( 5.9 , 7.3 ) 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. ( 5.10 , 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. ( 5.11 , 7.7 ) 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 Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including esomeprazole magnesium. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue esomeprazole magnesium if acute interstitial nephritis develops [ 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 C lostridium 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 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. 5.6 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 ( 7.3 ) and Clinical Pharmacology ( 12.3 ) ]. 5.7 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. 5.8 Hypomagnesemia 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. 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), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [ see Adverse Reactions (6.2) ]. 5.9 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 ( 7.3 ) ]. Avoid concomitant use of esomeprazole magnesium with St. John’s Wort or rifampin. 5.10 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 ) ]. 5.11 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 ( 7.7 ) ].

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Interstitial Nephritis [ see Warnings and Precautions ( 5.2 ) ] Clostridium difficile -Associated Diarrhea [ see Warnings and Precautions ( 5.3 ) ] Bone Fracture [ see Warnings and Precautions ( 5.4 ) ] Cutaneous and Systemic Lupus Erythematosus [ see Warnings and Precautions ( 5.5 ) ] Cyanocobalamin (Vitamin B-12) Deficiency [ see Warnings and Precautions ( 5.7 ) ] Hypomagnesemia [ see Warnings and Precautions ( 5.8 ) ] Most common adverse reactions ( 6.1 ): Adults (≥ 18 years) (incidence ≥ 1%) are headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth. Pediatric (1 to 17 years) (incidence ≥ 2%) are headache, diarrhea, abdominal pain, nausea, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-866-832-8537 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The safety of esomeprazole magnesium was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6 to 12 months. In general, esomeprazole magnesium was well tolerated in both short and long-term clinical trials. The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on esomeprazole magnesium 20 mg, 2,434 patients on esomeprazole magnesium 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse reactions (≥ 1%) in all three groups were headache (5.5, 5, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking esomeprazole magnesium or omeprazole. Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence < 1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular: flushing, hypertension, tachycardia; Endocrine: goiter; Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing: earache, tinnitus; Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive: dysmenorrhea, menstrual disorder, vaginitis; Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses: otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual: conjunctivitis, vision abnormal. The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone [see Clinical Pharmacology ( 12 ) ]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration. The incidence of treatment-related adverse reactions during 6 month maintenance treatment was similar to placebo. There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment. Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse reactions that were reported as possibly or probably related to esomeprazole magnesium were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%). Pediatrics The safety of esomeprazole magnesium was evaluated in 316 pediatric and adolescent patients aged 1 to 17 years in four clinical trials for the treatment of symptomatic GERD [ see Clinical Studies ( 14.2 ) ]. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (2.8%), headache (1.9%) and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years the most frequently reported (at least 2%) treatment-related adverse reactions in these patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%), and nausea (2%). No new safety concerns were identified in pediatric patients. Combination Treatment With Amoxicillin and Clarithromycin In clinical trials using combination therapy with esomeprazole magnesium plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using esomeprazole magnesium, amoxicillin, or clarithromycin alone. The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with esomeprazole magnesium alone. For more information on adverse reactions with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions sections. In clinical trials using combination therapy with esomeprazole magnesium plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed. For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions section. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of esomeprazole magnesium. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Blood and Lymphatic: agranulocytosis, pancytopenia; Eye: blurred vision; Gastrointestinal: pancreatitis, stomatitis, microscopic colitis; Hepatobiliary: hepatic failure, hepatitis with or without jaundice; Immune System: anaphylactic reaction/shock; systemic lupus erythematosus; Infections and Infestations: GI candidiasis, Clostridium difficile- associated diarrhea; Metabolism and Nutritional Disorders: hypomagnesemia, with or without hypocalcemia and/or hypokalemia; Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture; Nervous System: hepatic encephalopathy, taste disturbance; Psychiatric: aggression, agitation, depression, hallucination; Renal and Urinary: interstitial nephritis; Reproductive System and Breast: gynecomastia; Respiratory, Thoracic, and Mediastinal: bronchospasm; Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.