= 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Studies Experience\n\n 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 clinical practice.\n\n\n\n The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).\n\n\n\n Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.\n\n\n\n Table 2 lists adverse reactions that occurred in >= 0.2% patients who received DOTAREM.\n\n\n\n Table 2: Adverse Reactions in Clinical Trials \n Reaction Rate (%) n=2813 \n Nausea 0.6% \n Headache 0.5% \n Injection Site Pain 0.4% \n Injection Site Coldness 0.2% \n Burning Sensation 0.2% \n \n \n\n Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.\n\n\n\n Adverse Reactions in Pediatric Patients \n\n\n\n During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.\n\n\n\n 6.2 Postmarketing Experience\n\n The following additional adverse reactions have been identified during postmarketing use of DOTAREM. 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.\n\n\n\n Table 3: Adverse Reactions in the Postmarketing Experience \n System Organ Class Adverse Reaction \n \n Cardiac Disorders bradycardia, tachycardia, arrhythmia \n Immune System Disorders hypersensitivity /anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria \n Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor \n Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness \n Gastrointestinal Disorders diarrhea, salivary hypersecretion \n General Disorders and Administration Site Conditions malaise, fever \n Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM. \n Vascular Disorders superficial phlebitis \n"],"offsets":[[0,5005]]},{"id":"dotarem_section_S2","type":"boxed warnings","text":["\n\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. \n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1). \n * For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. \n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) \n \n\n See full prescribing information for complete boxed warning \n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \n\n\n\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1) \n"],"offsets":[[5006,7005]]},{"id":"dotarem_section_S3","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appear to increase the risk. ( 5.1 ) \n * Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.2 ) \n \n \n\n 5.1 Nephrogenic Systemic Fibrosis\n\n\n\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).\n\n\n\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\n\n\n\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12 )] .\n\n\n\n 5.2 Hypersensitivity Reactions\n\n\n\n Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment [see Adverse Reactions (6) ] .\n\n\n\n * Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. \n * Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \n * During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. \n 5.3 Acute Kidney Injury\n \n\n In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.\n\n\n\n 5.4 Extravasation and Injection Site Reactions\n\n\n\n Ensure catheter and venous patency before the injection of DOTAREM. Extravasation into tissues during DOTAREM administration may result in tissue irritation [see Nonclinical Toxicology ( 13.2 )] .\n"],"offsets":[[7006,11561]]}],"string":"[\n {\n \"id\": \"dotarem_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n GBCAs have been associated with a risk for NSF [see Warnings and Precautions ( 5.1 )] . NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.\\n\\n\\n\\n Hypersensitivity reactions and acute kidney injury are described in other sections of the labeling [see Warnings and Precautions ( 5.2 ) and ( 5.3 )] .\\n\\n\\n\\n EXCERPT: The most frequent (>= 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and burning sensation.\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact GUERBET LLC at 1-877-729-6679 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\\n\\n\\n \\n\\n 6.1 Clinical Studies Experience\\n\\n 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 clinical practice.\\n\\n\\n\\n The data described below reflect DOTAREM exposure in 2813 patients, representing 2672 adults and 141 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded the ethnic distribution was 74% Caucasian, 12% Asian, 4% Black, and 10% others. The average age was 53 years (range from 0.1 to 97 years).\\n\\n\\n\\n Overall, 3.9% of patients reported at least one adverse reaction, primarily occurring immediately or several days following DOTAREM administration. Most adverse reactions were mild or moderate in severity and transient in nature.\\n\\n\\n\\n Table 2 lists adverse reactions that occurred in >= 0.2% patients who received DOTAREM.\\n\\n\\n\\n Table 2: Adverse Reactions in Clinical Trials \\n Reaction Rate (%) n=2813 \\n Nausea 0.6% \\n Headache 0.5% \\n Injection Site Pain 0.4% \\n Injection Site Coldness 0.2% \\n Burning Sensation 0.2% \\n \\n \\n\\n Adverse reactions that occurred with a frequency < 0.2% in patients who received DOTAREM include: feeling cold, rash, somnolence, fatigue, dizziness, vomiting, pruritus, paresthesia, dysgeusia, pain in extremity, anxiety, hypertension, palpitations, oropharyngeal discomfort, serum creatinine increased and injection site reactions, including site inflammation, extravasation, pruritus, and warmth.\\n\\n\\n\\n Adverse Reactions in Pediatric Patients \\n\\n\\n\\n During clinical trials, 141 pediatric patients (7 aged < 24 months, 33 aged 2 - 5 years, 58 aged 6 - 11 years and 43 aged 12 - 17) received DOTAREM. Overall, 6 pediatric patients (4.3%) reported at least one adverse reaction following DOTAREM administration. The most frequently reported adverse reaction was headache (1.5%). Most adverse events were mild in severity and transient in nature, and all patients recovered without treatment.\\n\\n\\n\\n 6.2 Postmarketing Experience\\n\\n The following additional adverse reactions have been identified during postmarketing use of DOTAREM. 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.\\n\\n\\n\\n Table 3: Adverse Reactions in the Postmarketing Experience \\n System Organ Class Adverse Reaction \\n \\n Cardiac Disorders bradycardia, tachycardia, arrhythmia \\n Immune System Disorders hypersensitivity /anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria \\n Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor \\n Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness \\n Gastrointestinal Disorders diarrhea, salivary hypersecretion \\n General Disorders and Administration Site Conditions malaise, fever \\n Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with DOTAREM. \\n Vascular Disorders superficial phlebitis \\n\"\n ],\n \"offsets\": [\n [\n 0,\n 5005\n ]\n ]\n },\n {\n \"id\": \"dotarem_section_S2\",\n \"type\": \"boxed warnings\",\n \"text\": [\n \"\\n\\n BOXED WARNING: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\\n\\n WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. \\n\\n\\n\\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \\n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1). \\n * For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. \\n EXCERPT: WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) \\n \\n\\n See full prescribing information for complete boxed warning \\n\\n\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. \\n\\n\\n\\n * The risk for NSF appears highest among patients with:Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m2), orAcute kidney injury. \\n * Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing (5.1) \\n\"\n ],\n \"offsets\": [\n [\n 5006,\n 7005\n ]\n ]\n },\n {\n \"id\": \"dotarem_section_S3\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appear to increase the risk. ( 5.1 ) \\n * Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.2 ) \\n \\n \\n\\n 5.1 Nephrogenic Systemic Fibrosis\\n\\n\\n\\n Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 - 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following DOTAREM administration to Guerbet LLC (1-877-729-6679) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).\\n\\n\\n\\n Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.\\n\\n\\n\\n Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended DOTAREM dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12 )] .\\n\\n\\n\\n 5.2 Hypersensitivity Reactions\\n\\n\\n\\n Anaphylactic and anaphylactoid reactions have been reported with DOTAREM, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM administration and resolved with prompt emergency treatment [see Adverse Reactions (6) ] .\\n\\n\\n\\n * Before DOTAREM administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM. \\n * Administer DOTAREM only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. \\n * During and following DOTAREM administration, observe patients for signs and symptoms of hypersensitivity reactions. \\n 5.3 Acute Kidney Injury\\n \\n\\n In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction.\\n\\n\\n\\n 5.4 Extravasation and Injection Site Reactions\\n\\n\\n\\n Ensure catheter and venous patency before the injection of DOTAREM. 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}\n]","isConversational":false}}},{"rowIdx":92,"cells":{"id":{"kind":"string","value":"92"},"document_id":{"kind":"string","value":"breo"},"passages":{"kind":"list like","value":[{"id":"breo_section_S1","type":"adverse reactions","text":[" 6 ADVERSE REACTIONS\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. [See Warnings and Precautions (5.1).] \n\n\n\n Systemic and local corticosteroid use may result in the following:\n\n\n\n * Candida albicans infection [see Warnings and Precautions (5.4)] \n * Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)] \n * Immunosuppression [see Warnings and Precautions (5.6)] \n * Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] \n * Reduction in bone mineral density [see Warnings and Precautions (5.13)] \n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\n \n\n EXCERPT: * COPD: Most common adverse reactions (incidence greater than or equal to 3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. ( 6.1 ) \n * Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) \n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n \n\n \n\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\n\n The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.\n\n\n\n 6-Month Trials \n\n\n\n The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).\n\n\n\n Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.\n\n\n\n Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >=3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % \n Infections and infestations \n Nasopharyngitis \n 9 10 8 8 \n Upper respiratory tract infection \n 7 5 4 3 \n Oropharyngeal candidiasis a \n 5 2 3 2 \n Nervous system disorders \n Headache \n 7 9 7 5 \n a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.\n \n\n 12-Month Trials \n\n\n\n Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions (5.5)] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.\n\n\n\n 6.2 Clinical Trials Experience in Asthma\n\n BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks' duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and two long-term trials.\n\n\n\n 12-Week Trials \n\n\n\n Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adolescent and adult subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 2.\n\n\n\n Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >=2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % \n Infections and infestations \n Nasopharyngitis \n 10 7 7 \n Oral candidiasis a \n 2 2 0 \n Nervous system disorders \n Headache \n 5 4 4 \n Respiratory, thoracic, and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Dysphonia \n 2 1 0 \n a Includes oral candidiasis and oropharyngeal candidiasis.\n \n\n Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 3.\n\n\n\n Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >=2% Incidence in Subjects with Asthma (Trial 2) \n\n\n\n\n Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % \n Nervous system disorders \n Headache \n 8 8 9 \n Infections and infestations \n Nasopharyngitis \n 7 6 7 \n Influenza \n 3 3 1 \n Upper respiratory tract infection \n 2 2 3 \n Sinusitis \n 2 1 <1 \n Bronchitis \n 2 <1 2 \n Respiratory, thoracic and mediastinal disorders \n Oropharyngeal pain \n 2 2 1 \n Cough \n 1 2 1 \n 24-Week Trial \n \n\n Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adolescent and adult subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.\n\n\n\n 12-Month Trial \n\n\n\n Long-term safety data is based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adolescent and adult subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.\n\n\n\n Exacerbation Trial \n\n\n\n In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial.\n\n\n\n 6.3 Postmarketing Experience\n\n In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. 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 events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to BREO ELLIPTA or a combination of these factors.\n\n\n\n Cardiac Disorders \n\n\n\n Palpitations, tachycardia.\n\n\n\n Immune System Disorders \n\n\n\n Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.\n\n\n\n Musculoskeletal and Connective Tissue Disorders \n\n\n\n Muscle spasms.\n\n\n\n Nervous System Disorders \n\n\n\n Tremor.\n\n\n\n Psychiatric Disorders \n\n\n\n Nervousness.\n"],"offsets":[[0,16091]]},{"id":"breo_section_S2","type":"boxed warnings","text":["\n\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\n\n WARNING: ASTHMA-RELATED DEATH\n\n Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. \n\n\n\n Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)] . \n\n\n\n EXCERPT: WARNING: ASTHMA-RELATED DEATH\n\n\n\n See full prescribing information for complete boxed warning. \n\n\n\n * Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) \n * When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1) \n"],"offsets":[[16092,19204]]},{"id":"breo_section_S3","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations. ( 5.1 ) \n * Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) \n * Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) \n * Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) \n * Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) \n * Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. ( 5.6 ) \n * Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) \n * Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) \n * If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) \n * Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) \n * Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) \n * Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) \n * Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) \n * Be alert to hypokalemia and hyperglycemia. ( 5.16 ) \n \n \n\n 5.1 Asthma-Related Death\n\n\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. \n\n\n\n A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.\n\n\n\n Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.\n\n\n\n 5.2 Deterioration of Disease and Acute Episodes\n\n\n\n BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.\n\n\n\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.\n\n\n\n Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.\n\n\n\n BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.\n\n\n\n When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.\n\n\n\n 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists\n\n\n\n BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, 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 BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.\n\n\n\n 5.4 Local Effects of Inhaled Corticosteroids\n\n\n\n In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.\n\n\n\n 5.5 Pneumonia\n\n\n\n An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.\n\n\n\n In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).\n\n\n\n 5.6 Immunosuppression\n\n\n\n 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 been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is 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.\n\n\n\n Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.\n\n\n\n 5.7 Transferring Patients from Systemic Corticosteroid Therapy\n\n\n\n Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma 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.\n\n\n\n Patients who have been previously maintained on 20 mg or more 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 BREO ELLIPTA may control COPD or 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.\n\n\n\n During periods of stress, a severe COPD exacerbation, 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 warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.\n\n\n\n Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV1or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.\n\n\n\n Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).\n\n\n\n During withdrawal from oral corticosteroids, 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.\n\n\n\n 5.8 Hypercorticism and Adrenal Suppression\n\n\n\n Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .\n\n\n\n Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA 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.\n\n\n\n It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.\n\n\n\n 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors\n\n\n\n Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. \n\n\n\n 5.10 Paradoxical Bronchospasm\n\n\n\n As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.\n\n\n\n 5.11 Hypersensitivity Reactions, Including Anaphylaxis\n\n\n\n Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .\n\n\n\n 5.12 Cardiovascular Effects\n\n\n\n Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.\n\n\n\n In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\n\n\n\n 5.13 Reduction in Bone Mineral Density\n\n\n\n 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, postmenopausal status, tobacco use, advanced 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. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient's COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.\n\n\n\n 5.14 Glaucoma and Cataracts\n\n\n\n Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.\n\n\n\n 5.15 Coexisting Conditions\n\n\n\n BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.\n\n\n\n 5.16 Hypokalemia and Hyperglycemia\n\n\n\n Beta-adrenergic agonist medicines 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. Beta-agonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.\n\n\n\n 5.17 Effect on Growth\n\n\n\n Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations (8.4).] \n"],"offsets":[[19205,38763]]}],"string":"[\n {\n \"id\": \"breo_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. [See Warnings and Precautions (5.1).] \\n\\n\\n\\n Systemic and local corticosteroid use may result in the following:\\n\\n\\n\\n * Candida albicans infection [see Warnings and Precautions (5.4)] \\n * Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)] \\n * Immunosuppression [see Warnings and Precautions (5.6)] \\n * Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)] \\n * Reduction in bone mineral density [see Warnings and Precautions (5.13)] \\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.\\n \\n\\n EXCERPT: * COPD: Most common adverse reactions (incidence greater than or equal to 3%) are nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis. ( 6.1 ) \\n * Asthma: Most common adverse reactions (incidence greater than or equal to 2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 6.2 ) \\n To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n \\n\\n \\n\\n 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease\\n\\n The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.\\n\\n\\n\\n 6-Month Trials \\n\\n\\n\\n The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack-years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).\\n\\n\\n\\n Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.\\n\\n\\n\\n Table 1. Adverse Reactions with BREO ELLIPTA 100/25 with >=3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % \\n Infections and infestations \\n Nasopharyngitis \\n 9 10 8 8 \\n Upper respiratory tract infection \\n 7 5 4 3 \\n Oropharyngeal candidiasis a \\n 5 2 3 2 \\n Nervous system disorders \\n Headache \\n 7 9 7 5 \\n a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis.\\n \\n\\n 12-Month Trials \\n\\n\\n\\n Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions (5.5)] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia.\\n\\n\\n\\n 6.2 Clinical Trials Experience in Asthma\\n\\n BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks' duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and two long-term trials.\\n\\n\\n\\n 12-Week Trials \\n\\n\\n\\n Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adolescent and adult subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 2.\\n\\n\\n\\n Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with >=2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % \\n Infections and infestations \\n Nasopharyngitis \\n 10 7 7 \\n Oral candidiasis a \\n 2 2 0 \\n Nervous system disorders \\n Headache \\n 5 4 4 \\n Respiratory, thoracic, and mediastinal disorders \\n Oropharyngeal pain \\n 2 2 1 \\n Dysphonia \\n 2 1 0 \\n a Includes oral candidiasis and oropharyngeal candidiasis.\\n \\n\\n Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adolescent and adult subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 3.\\n\\n\\n\\n Table 3. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with >=2% Incidence in Subjects with Asthma (Trial 2) \\n\\n\\n\\n\\n Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % \\n Nervous system disorders \\n Headache \\n 8 8 9 \\n Infections and infestations \\n Nasopharyngitis \\n 7 6 7 \\n Influenza \\n 3 3 1 \\n Upper respiratory tract infection \\n 2 2 3 \\n Sinusitis \\n 2 1 <1 \\n Bronchitis \\n 2 <1 2 \\n Respiratory, thoracic and mediastinal disorders \\n Oropharyngeal pain \\n 2 2 1 \\n Cough \\n 1 2 1 \\n 24-Week Trial \\n \\n\\n Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adolescent and adult subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia.\\n\\n\\n\\n 12-Month Trial \\n\\n\\n\\n Long-term safety data is based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adolescent and adult subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 2 and 3, adverse reactions occurring in greater than or equal to 2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia.\\n\\n\\n\\n Exacerbation Trial \\n\\n\\n\\n In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of one or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age-group [see Use in Specific Populations (8.4)] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial.\\n\\n\\n\\n 6.3 Postmarketing Experience\\n\\n In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. 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 events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to BREO ELLIPTA or a combination of these factors.\\n\\n\\n\\n Cardiac Disorders \\n\\n\\n\\n Palpitations, tachycardia.\\n\\n\\n\\n Immune System Disorders \\n\\n\\n\\n Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.\\n\\n\\n\\n Musculoskeletal and Connective Tissue Disorders \\n\\n\\n\\n Muscle spasms.\\n\\n\\n\\n Nervous System Disorders \\n\\n\\n\\n Tremor.\\n\\n\\n\\n Psychiatric Disorders \\n\\n\\n\\n Nervousness.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 16091\n ]\n ]\n },\n {\n \"id\": \"breo_section_S2\",\n \"type\": \"boxed warnings\",\n \"text\": [\n \"\\n\\n BOXED WARNING: WARNING: ASTHMA-RELATED DEATH\\n\\n WARNING: ASTHMA-RELATED DEATH\\n\\n Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. \\n\\n\\n\\n Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids [see Warnings and Precautions (5.1)] . \\n\\n\\n\\n EXCERPT: WARNING: ASTHMA-RELATED DEATH\\n\\n\\n\\n See full prescribing information for complete boxed warning. \\n\\n\\n\\n * Long-acting beta2-adrenergic agonists (LABA), such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths. This finding with salmeterol is considered a class effect of all LABA. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids (ICS) or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1) \\n * When treating patients with asthma, only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an ICS, or whose disease severity clearly warrants initiation of treatment with both an ICS and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an ICS. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose ICS.(1.2, 5.1) \\n\"\n ],\n \"offsets\": [\n [\n 16092,\n 19204\n ]\n ]\n },\n {\n \"id\": \"breo_section_S3\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * LABA increase the risk of asthma-related death and asthma-related hospitalizations. Prescribe only for recommended patient populations. ( 5.1 ) \\n * Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) \\n * Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) \\n * Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) \\n * Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) \\n * Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; 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. ( 5.6 ) \\n * Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) \\n * Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) \\n * If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) \\n * Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) \\n * Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) \\n * Close monitoring for glaucoma and cataracts is warranted. ( 5.14 ) \\n * Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) \\n * Be alert to hypokalemia and hyperglycemia. ( 5.16 ) \\n \\n \\n\\n 5.1 Asthma-Related Death\\n\\n\\n\\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe BREO ELLIPTA for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue BREO ELLIPTA) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use BREO ELLIPTA for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids. \\n\\n\\n\\n A 28-week, placebo-controlled, US trial that compared the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted.\\n\\n\\n\\n Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.\\n\\n\\n\\n 5.2 Deterioration of Disease and Acute Episodes\\n\\n\\n\\n BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate.\\n\\n\\n\\n COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation.\\n\\n\\n\\n Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of BREO ELLIPTA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA.\\n\\n\\n\\n BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.\\n\\n\\n\\n When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.\\n\\n\\n\\n 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-Acting Beta2-Agonists\\n\\n\\n\\n BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, 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 BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.\\n\\n\\n\\n 5.4 Local Effects of Inhaled Corticosteroids\\n\\n\\n\\n In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.\\n\\n\\n\\n 5.5 Pneumonia\\n\\n\\n\\n An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.\\n\\n\\n\\n In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (less than 1% for each treatment group).\\n\\n\\n\\n 5.6 Immunosuppression\\n\\n\\n\\n 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 been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is 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.\\n\\n\\n\\n Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.\\n\\n\\n\\n 5.7 Transferring Patients from Systemic Corticosteroid Therapy\\n\\n\\n\\n Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma 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.\\n\\n\\n\\n Patients who have been previously maintained on 20 mg or more 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 BREO ELLIPTA may control COPD or 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.\\n\\n\\n\\n During periods of stress, a severe COPD exacerbation, 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 warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack.\\n\\n\\n\\n Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV1or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.\\n\\n\\n\\n Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).\\n\\n\\n\\n During withdrawal from oral corticosteroids, 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.\\n\\n\\n\\n 5.8 Hypercorticism and Adrenal Suppression\\n\\n\\n\\n Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)] .\\n\\n\\n\\n Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA 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.\\n\\n\\n\\n It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered.\\n\\n\\n\\n 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors\\n\\n\\n\\n Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. \\n\\n\\n\\n 5.10 Paradoxical Bronchospasm\\n\\n\\n\\n As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.\\n\\n\\n\\n 5.11 Hypersensitivity Reactions, Including Anaphylaxis\\n\\n\\n\\n Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications (4)] .\\n\\n\\n\\n 5.12 Cardiovascular Effects\\n\\n\\n\\n Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.\\n\\n\\n\\n In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.\\n\\n\\n\\n 5.13 Reduction in Bone Mineral Density\\n\\n\\n\\n 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, postmenopausal status, tobacco use, advanced 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. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient's COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered.\\n\\n\\n\\n 5.14 Glaucoma and Cataracts\\n\\n\\n\\n Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.\\n\\n\\n\\n 5.15 Coexisting Conditions\\n\\n\\n\\n BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.\\n\\n\\n\\n 5.16 Hypokalemia and Hyperglycemia\\n\\n\\n\\n Beta-adrenergic agonist medicines 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. Beta-agonist medications may produce transient hyperglycemia in some patients. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum glucose or potassium.\\n\\n\\n\\n 5.17 Effect on Growth\\n\\n\\n\\n Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. 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REACTIONS\n\n EXCERPT: Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Study Experience\n\n 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.\n\n\n\n During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration.\n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Serious adverse reactions were not observed in the AdreView clinical study. Adverse reactions were all mild to moderate in severity and were predominantly isolated occurrences (<= 2 patients) of one of the following reactions: dizziness, rash, pruritus, flushing or injection site hemorrhage.\n\n\n\n Congestive Heart Failure \n\n\n\n No serious adverse reactions to AdreView were observed in clinical studies. Adverse reactions that occurred with a frequency > 1% were associated with the injection site (1.3%), problems such as hematoma and bruising. The other most common reactions were flushing (0.3%) and headache (0.4%). The adverse reactions were predominantly of mild to moderate intensity.\n\n\n\n 6.2 Postmarketing Experience\n\n Because postmarketing 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.\n\n\n\n Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].\n"],"offsets":[[0,2181]]},{"id":"adreview_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) \n * Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) \n * AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) \n * Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) \n * Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) \n \n \n\n 5.1 Hypersensitivity Reactions\n\n\n\n Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration [ see Adverse Reactions (6.2) ].\n\n\n\n 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications\n\n\n\n Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. If the AdreView imaging information is essential for clinical care, consider the withdrawal of the following categories of medications if the withdrawal can be accomplished safely: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), and sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine). The period of time necessary to discontinue any specific medication prior to AdreView dosing has not been established [ see Drug Interactions (7) ]. \n\n\n\n Pheochromocytoma and Neuroblastoma \n\n\n\n Drugs which interfere with norepinephrine uptake in neuroendocrine tumors may lead to false negative imaging results. When medically feasible, stop these drugs before AdreView administration and monitor patients for the occurrence of clinically significant withdrawal symptoms, especially patients with elevated levels of circulating catecholamines and their metabolites. \n\n\n\n Congestive Heart Failure \n\n\n\n Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging (see above). AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging. In clinical trials, patients were not eligible for AdreView imaging if they were receiving medications in the above categories and the risks for medication withdrawal were unacceptable or if they were not clinically stable (e.g., experiencing continuing chest pain, hemodynamic instability, or clinically significant arrhythmia). \n\n\n\n 5.3 Risks for Benzyl Alcohol Toxicity in Infants\n\n\n\n AdreView contains benzyl alcohol at a concentration of 10.3 mg/mL. Benzyl alcohol has been associated with a fatal \"Gasping Syndrome\" in premature infants and infants of low birth weight. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol [ see Description (11) ].\n\n\n\n Observe infants for signs or symptoms of benzyl alcohol toxicity following AdreView administration. AdreView safety and effectiveness have not been established in neonates (pediatric patients below the age of 1 month).\n\n\n\n 5.4 Increased Radiation Exposure in Patients with Severe Renal Impairment\n\n\n\n AdreView is cleared by glomerular filtration and is not dialyzable. The radiation dose to patients with severe renal impairment may be increased due to the delayed elimination of the drug. Delayed AdreView clearance may also reduce the target to background ratios and decrease the quality of scintigraphic images. These risks importantly may limit the role of AdreView in the diagnostic evaluation of patients with severe renal impairment. AdreView safety and efficacy have not been established in these patients [ see Clinical Pharmacology (12.2) ].\n\n\n\n 5.5 Imaging Errors due to Conditions that Affect the Sympathetic Nervous System\n\n\n\n Individuals with conditions that affect the sympathetic nervous system, e.g., Parkinsonian syndromes such as Parkinson's disease or multiple system atrophy, may show decreased cardiac uptake of AdreView independent of heart disease. \n\n\n\n 5.6 Thyroid Accumulation\n\n\n\n Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia [ see Dosage and Administration (2.2) ]. \n\n\n\n 5.7 Hypertension\n\n\n\n Assess the patient's pulse and blood pressure before and intermittently for 30 minutes after AdreView administration. AdreView may increase release of norepinephrine from chromaffin granules and produce a transient episode of hypertension, although this was not observed in the clinical studies. Prior to AdreView administration, ensure emergency cardiac and anti-hypertensive treatments are readily available.\n"],"offsets":[[2182,8329]]}],"string":"[\n {\n \"id\": \"adreview_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Study Experience\\n\\n 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.\\n\\n\\n\\n During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration.\\n\\n\\n\\n Pheochromocytoma and Neuroblastoma \\n\\n\\n\\n Serious adverse reactions were not observed in the AdreView clinical study. 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The adverse reactions were predominantly of mild to moderate intensity.\\n\\n\\n\\n 6.2 Postmarketing Experience\\n\\n Because postmarketing 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.\\n\\n\\n\\n Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2181\n ]\n ]\n },\n {\n \"id\": \"adreview_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) \\n * Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) \\n * AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) \\n * Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) \\n * Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) \\n \\n \\n\\n 5.1 Hypersensitivity Reactions\\n\\n\\n\\n Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration [ see Adverse Reactions (6.2) ].\\n\\n\\n\\n 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications\\n\\n\\n\\n Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. 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widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.\n\n\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Seizures, Anaphylaxis, and Urinary Tract Infections.\n\n\n\n EXCERPT: The most common adverse events (incidence >=2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Controlled Clinical Trials Experience\n\n In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).\n\n\n\n Table 1 lists adverse reactions that occurred in >=2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials.\n\n\n\n Table 1: Adverse reactions with an incidence >=2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials \n Adverse Reaction Placebo(N=238) AMPYRA10 mg twice daily(N=400) \n \n Urinary tract infection 8% 12% \n Insomnia 4% 9% \n Dizziness 4% 7% \n Headache 4% 7% \n Nausea 3% 7% \n Asthenia 4% 7% \n Back pain 2% 5% \n Balance disorder 1% 5% \n Multiple sclerosis relapse 3% 4% \n Paresthesia 3% 4% \n Nasopharyngitis 2% 4% \n Constipation 2% 3% \n Dyspepsia 1% 2% \n Pharyngolaryngeal pain 1% 2% \n 6.2 Other Adverse Reactions\n AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13-0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21-6.28).\n"],"offsets":[[0,4371]]},{"id":"ampyra_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs ( 5.1 ) \n * AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) \n * AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs ( 5.4 ) \n \n \n\n 5.1 Seizures\n\n\n\n AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9-14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.\n\n\n\n AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in AMPYRA clinical studies. AMPYRA should be discontinued and not restarted in patients who experience a seizure while on treatment. AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] .\n\n\n\n 5.2 Renal Impairment\n\n\n\n AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4) ]. \n\n\n\n Because patients with moderate to severe renal impairment (CrCl <=50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4) ] .\n\n\n\n In patients with mild renal impairment (CrCl 51-80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1) ] .\n\n\n\n 5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine\n\n\n\n AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Patients should discontinue use of any product containing 4-aminopyridine prior to initiating treatment with AMPYRA in order to reduce the potential for dose-related adverse reactions.\n\n\n\n 5.4 Anaphylaxis\n\n\n\n AMPYRA can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Patients should be informed of the signs and symptoms of anaphylaxis and instructed to discontinue AMPYRA and seek immediate medical care should these signs and symptoms occur ( 17.3 ).\n\n\n\n 5.5 Urinary Tract Infections\n\n\n\n Urinary tract infections (UTIs) were reported more frequently as adverse reactions in controlled studies in patients receiving AMPYRA 10 mg twice daily (12%) as compared to placebo (8%). 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To report SUSPECTED ADVERSE REACTIONS, contact Acorda Therapeutics at 1-800-367-5109 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Controlled Clinical Trials Experience\\n\\n In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with AMPYRA 10 mg twice daily experienced one or more treatment emergent adverse events leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The treatment emergent adverse events leading to discontinuation of at least 2 patients treated with AMPYRA and that led to discontinuation more frequently compared to placebo were headache (AMPYRA 0.5%, placebo 0%), balance disorder (AMPYRA 0.5%, placebo 0%), dizziness (AMPYRA 0.5%, placebo 0%), and confusional state (AMPYRA 0.3%, placebo 0%).\\n\\n\\n\\n Table 1 lists adverse reactions that occurred in >=2% of patients treated with AMPYRA 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials.\\n\\n\\n\\n Table 1: Adverse reactions with an incidence >=2% of AMPYRA treated MS patients, and more frequent with AMPYRA compared to placebo in controlled clinical trials \\n Adverse Reaction Placebo(N=238) AMPYRA10 mg twice daily(N=400) \\n \\n Urinary tract infection 8% 12% \\n Insomnia 4% 9% \\n Dizziness 4% 7% \\n Headache 4% 7% \\n Nausea 3% 7% \\n Asthenia 4% 7% \\n Back pain 2% 5% \\n Balance disorder 1% 5% \\n Multiple sclerosis relapse 3% 4% \\n Paresthesia 3% 4% \\n Nasopharyngitis 2% 4% \\n Constipation 2% 3% \\n Dyspepsia 1% 2% \\n Pharyngolaryngeal pain 1% 2% \\n 6.2 Other Adverse Reactions\\n AMPYRA has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with AMPYRA for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with AMPYRA in patients with MS as follows: AMPYRA 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13-0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21-6.28).\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 4371\n ]\n ]\n },\n {\n \"id\": \"ampyra_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * AMPYRA can cause seizures; the risk of seizures increases with increasing AMPYRA doses; discontinue AMPYRA and do not restart if a seizure occurs ( 5.1 ) \\n * AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same ( 5.3 ) \\n * AMPYRA can cause anaphylaxis. Discontinue and do not restart AMPYRA if this occurs ( 5.4 ) \\n \\n \\n\\n 5.1 Seizures\\n\\n\\n\\n AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily in controlled clinical studies of 9-14 weeks duration with dalfampridine in patients with MS. In open label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.\\n\\n\\n\\n AMPYRA has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. 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AMPYRA is contraindicated in patients with a history of seizures [see Contraindications (4) ] .\\n\\n\\n\\n 5.2 Renal Impairment\\n\\n\\n\\n AMPYRA is eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.4) ]. \\n\\n\\n\\n Because patients with moderate to severe renal impairment (CrCl <=50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, AMPYRA is contraindicated in these patients [see Contraindications (4) ] .\\n\\n\\n\\n In patients with mild renal impairment (CrCl 51-80 mL/min), AMPYRA plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1) ] .\\n\\n\\n\\n 5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine\\n\\n\\n\\n AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. 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( 6.1 )\n \n\n To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice.\n\n\n\n The most common adverse reactions (incidence >=10% and >=2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.\n\n\n\n Adverse Reactions in Placebo-Controlled Trials \n\n\n\n In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. \n\n\n\n The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.\n\n\n\n Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at >= 2% higher incidence than placebo \n TECFIDERA N=769 % Placebo N=771 % \n \n Flushing 40 6 \n Abdominal pain 18 10 \n Diarrhea 14 11 \n Nausea 12 9 \n Vomiting 9 5 \n Pruritus 8 4 \n Rash 8 3 \n Albumin urine present 6 4 \n Erythema 5 1 \n Dyspepsia 5 3 \n Aspartate aminotransferase increased 4 2 \n Lymphopenia 2 <1 \n Gastrointestinal \n \n\n TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.\n\n\n\n Hepatic Transaminases \n\n\n\n An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to >= 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases >= 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.\n\n\n\n Eosinophilia \n\n\n\n A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.\n\n\n\n Adverse Reactions in Placebo-Controlled and Uncontrolled Studies \n\n\n\n In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.\n"],"offsets":[[0,5083]]},{"id":"tecfidera_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA if these occur. ( 5.1 ) \n * Progressive multifocal leukoencephalopathy (PML): Withhold TECFIDERA at the first sign or symptom suggestive of PML. ( 5.2 ) \n * Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.3 ) \n \n \n\n 5.1 Anaphylaxis and Angioedema\n\n\n\n TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.\n\n\n\n 5.2 Progressive Multifocal Leukoencephalopathy\n\n\n\n A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received TECFIDERA for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions ( 5.3 )] . The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.\n\n\n\n At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.\n\n\n\n 5.3 Lymphopenia\n\n\n\n TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or 0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 10 9 /L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.\n\n\n\n Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5 x 10 9 /L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.\n\n\n\n 5.4 Flushing\n\n\n\n TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] .\n"],"offsets":[[5084,10394]]}],"string":"[\n {\n \"id\": \"tecfidera_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n The following important adverse reactions are described elsewhere in labeling:\\n\\n\\n\\n * Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.1 )]. \\n * Progressive multifocal leukoencephalopathy [see Warnings and Precautions ( 5.2 )]. \\n * Lymphopenia [see Warnings and Precautions ( 5.3 )]. \\n * Flushing [see Warnings and Precautions ( 5.4 )]. \\n EXCERPT: Most common adverse reactions (incidence >=10% and >=2% placebo) were flushing, abdominal pain, diarrhea, and nausea. ( 6.1 )\\n \\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 clinical practice.\\n\\n\\n\\n The most common adverse reactions (incidence >=10% and >=2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.\\n\\n\\n\\n Adverse Reactions in Placebo-Controlled Trials \\n\\n\\n\\n In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies ( 14 )]. \\n\\n\\n\\n The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.\\n\\n\\n\\n Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at >= 2% higher incidence than placebo \\n TECFIDERA N=769 % Placebo N=771 % \\n \\n Flushing 40 6 \\n Abdominal pain 18 10 \\n Diarrhea 14 11 \\n Nausea 12 9 \\n Vomiting 9 5 \\n Pruritus 8 4 \\n Rash 8 3 \\n Albumin urine present 6 4 \\n Erythema 5 1 \\n Dyspepsia 5 3 \\n Aspartate aminotransferase increased 4 2 \\n Lymphopenia 2 <1 \\n Gastrointestinal \\n \\n\\n TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA.\\n\\n\\n\\n Hepatic Transaminases \\n\\n\\n\\n An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase and aspartate aminotransferase to >= 3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases >= 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo.\\n\\n\\n\\n Eosinophilia \\n\\n\\n\\n A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.\\n\\n\\n\\n Adverse Reactions in Placebo-Controlled and Uncontrolled Studies \\n\\n\\n\\n In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 5083\n ]\n ]\n },\n {\n \"id\": \"tecfidera_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Anaphylaxis and angioedema: Discontinue and do not restart TECFIDERA if these occur. ( 5.1 ) \\n * Progressive multifocal leukoencephalopathy (PML): Withhold TECFIDERA at the first sign or symptom suggestive of PML. ( 5.2 ) \\n * Lymphopenia: Obtain a CBC including lymphocyte count before initiating TECFIDERA, after 6 months, and every 6 to 12 months thereafter. Consider interruption of TECFIDERA if lymphocyte counts <0.5 x 10 9 /L persist for more than six months. ( 5.3 ) \\n \\n \\n\\n 5.1 Anaphylaxis and Angioedema\\n\\n\\n\\n TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.\\n\\n\\n\\n 5.2 Progressive Multifocal Leukoencephalopathy\\n\\n\\n\\n A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received TECFIDERA for 4 years while enrolled in a clinical trial. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions ( 5.3 )] . The role of lymphopenia in this case is unknown. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.\\n\\n\\n\\n At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.\\n\\n\\n\\n 5.3 Lymphopenia\\n\\n\\n\\n TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x10 9 /L (lower limit of normal 0.91x10 9 /L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x10 9 /L or 0.5x10 9 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 9 /L for 3.5 years) [see Warnings and Precautions ( 5.2 )] . In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 10 9 /L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 9 /L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.\\n\\n\\n\\n Before initiating treatment with TECFIDERA, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts <0.5 x 10 9 /L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of TECFIDERA, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.\\n\\n\\n\\n 5.4 Flushing\\n\\n\\n\\n TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not life-threatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration ( 2.1 ) and Clinical Pharmacology ( 12.3 )] .\\n\"\n ],\n \"offsets\": [\n [\n 5084,\n 10394\n ]\n ]\n }\n]","isConversational":false},"entities":{"kind":"list like","value":[{"id":"tecfidera_entity_M1","type":"AdverseReaction","text":["Anaphylaxis"],"offsets":[[113,124]],"normalized":[]},{"id":"tecfidera_entity_M2","type":"AdverseReaction","text":["Angioedema"],"offsets":[[129,139]],"normalized":[]},{"id":"tecfidera_entity_M3","type":"AdverseReaction","text":["Progressive multifocal 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1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n\n\n\n \n\n 6.1 Clinical Trials Experience\n\n 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 clinical practice.\n\n\n\n In clinical studies, 555 patients were exposed to Amyvid. Amyvid caused no serious adverse reactions in the studies and the reported adverse reactions were predominantly mild to moderate in severity. The adverse reactions reported in more than one subject within the studies are shown in Table 2 .\n\n\n\n Table 2: Adverse Reactions Reported in Clinical Trials (N=555 patients) \n a Includes the terms blood pressure increased and hypertension. \n b Includes the terms injection site haemorrhage, injection site irritation, and injection site pain. \n c Includes the terms feeling cold and chills. \n \n Adverse Reactions N (Percent of patients) \n Headache 10 (1.8%) \n Musculoskeletal pain 4 (0.7%) \n Blood pressure increased a 4 (0.7%) \n Nausea 4 (0.7%) \n Fatigue 3 (0.5%) \n Injection site reaction b 3 (0.5%) \n Anxiety 2 (0.4%) \n Back pain 2 (0.4%) \n Claustrophobia 2 (0.4%) \n Dizziness 2 (0.4%) \n Feeling cold c 2 (0.4%) \n Insomnia 2 (0.4%) \n Neck pain 2 (0.4%) \n Other adverse reactions occurred at lower frequencies and included infusion site rash, dysgeusia, pruritis, urticaria, and flushing.\n"],"offsets":[[0,2986]]},{"id":"amyvid_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n EXCERPT: * Image interpretation errors (especially false negatives) have been observed ( 5.1 ). \n * Radiation risk: Amyvid, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.2 ). \n \n \n\n 5.1 Risk for Image Misinterpretation and other Errors\n\n\n\n Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation [see Clinical Studies ( 14 )] .\n\n\n\n Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors. Other errors may be due to extensive brain atrophy that limits the ability to distinguish gray and white matter on the Amyvid scan as well as motion artifacts that distort the image.\n\n\n\n Amyvid scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\n\n\n\n 5.2 Radiation Risk\n\n\n\n Amyvid, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 )] .\n"],"offsets":[[2987,4595]]}],"string":"[\n {\n \"id\": \"amyvid_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: The most common reported adverse reaction was headache, occurring in 2% of patients, followed by musculoskeletal pain, blood pressure increased, fatigue, nausea, and injection site reaction, all occurring in <1% of patients ( 6 ).\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n 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 clinical practice.\\n\\n\\n\\n In clinical studies, 555 patients were exposed to Amyvid. Amyvid caused no serious adverse reactions in the studies and the reported adverse reactions were predominantly mild to moderate in severity. The adverse reactions reported in more than one subject within the studies are shown in Table 2 .\\n\\n\\n\\n Table 2: Adverse Reactions Reported in Clinical Trials (N=555 patients) \\n a Includes the terms blood pressure increased and hypertension. \\n b Includes the terms injection site haemorrhage, injection site irritation, and injection site pain. \\n c Includes the terms feeling cold and chills. \\n \\n Adverse Reactions N (Percent of patients) \\n Headache 10 (1.8%) \\n Musculoskeletal pain 4 (0.7%) \\n Blood pressure increased a 4 (0.7%) \\n Nausea 4 (0.7%) \\n Fatigue 3 (0.5%) \\n Injection site reaction b 3 (0.5%) \\n Anxiety 2 (0.4%) \\n Back pain 2 (0.4%) \\n Claustrophobia 2 (0.4%) \\n Dizziness 2 (0.4%) \\n Feeling cold c 2 (0.4%) \\n Insomnia 2 (0.4%) \\n Neck pain 2 (0.4%) \\n Other adverse reactions occurred at lower frequencies and included infusion site rash, dysgeusia, pruritis, urticaria, and flushing.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2986\n ]\n ]\n },\n {\n \"id\": \"amyvid_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n EXCERPT: * Image interpretation errors (especially false negatives) have been observed ( 5.1 ). \\n * Radiation risk: Amyvid, similar to all radiopharmaceuticals, contributes to a patient's long-term cumulative radiation exposure. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure ( 2.1 , 5.2 ). \\n \\n \\n\\n 5.1 Risk for Image Misinterpretation and other Errors\\n\\n\\n\\n Errors may occur in the Amyvid estimation of brain neuritic plaque density during image interpretation [see Clinical Studies ( 14 )] .\\n\\n\\n\\n Image interpretation should be performed independently of the patient's clinical information. The use of clinical information in the interpretation of Amyvid images has not been evaluated and may lead to errors. Other errors may be due to extensive brain atrophy that limits the ability to distinguish gray and white matter on the Amyvid scan as well as motion artifacts that distort the image.\\n\\n\\n\\n Amyvid scan results are indicative of the brain neuritic amyloid plaque content only at the time of image acquisition and a negative scan result does not preclude the development of brain amyloid in the future.\\n\\n\\n\\n 5.2 Radiation Risk\\n\\n\\n\\n Amyvid, similar to other radiopharmaceuticals, contributes to a patient's overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling to protect patients and health care workers from unintentional radiation exposure [see Dosage and Administration ( 2.1 )] .\\n\"\n ],\n \"offsets\": [\n [\n 2987,\n 4595\n ]\n ]\n }\n]","isConversational":false},"entities":{"kind":"list like","value":[{"id":"amyvid_entity_M1","type":"AdverseReaction","text":["headache"],"offsets":[[84,92]],"normalized":[]},{"id":"amyvid_entity_M2","type":"AdverseReaction","text":["musculoskeletal pain"],"offsets":[[135,155]],"normalized":[]},{"id":"amyvid_entity_M3","type":"AdverseReaction","text":["blood pressure increased"],"offsets":[[157,181]],"normalized":[]},{"id":"amyvid_entity_M4","type":"AdverseReaction","text":["fatigue"],"offsets":[[183,190]],"normalized":[]},{"id":"amyvid_entity_M5","type":"AdverseReaction","text":["nausea"],"offsets":[[192,198]],"normalized":[]},{"id":"amyvid_entity_M6","type":"AdverseReaction","text":["injection site 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reaction"],"offsets":[[1998,2021]],"normalized":[]},{"id":"amyvid_entity_M20","type":"AdverseReaction","text":["Anxiety"],"offsets":[[2104,2111]],"normalized":[]},{"id":"amyvid_entity_M21","type":"AdverseReaction","text":["Back pain"],"offsets":[[2210,2219]],"normalized":[]},{"id":"amyvid_entity_M22","type":"AdverseReaction","text":["Claustrophobia"],"offsets":[[2316,2330]],"normalized":[]},{"id":"amyvid_entity_M23","type":"AdverseReaction","text":["Dizziness"],"offsets":[[2422,2431]],"normalized":[]},{"id":"amyvid_entity_M24","type":"AdverseReaction","text":["Feeling cold"],"offsets":[[2528,2540]],"normalized":[]},{"id":"amyvid_entity_M25","type":"AdverseReaction","text":["Insomnia"],"offsets":[[2634,2642]],"normalized":[]},{"id":"amyvid_entity_M26","type":"AdverseReaction","text":["Neck pain"],"offsets":[[2740,2749]],"normalized":[]},{"id":"amyvid_entity_M27","type":"AdverseReaction","text":["infusion site rash"],"offsets":[[2920,2938]],"normalized":[]},{"id":"amyvid_entity_M28","type":"AdverseReaction","text":["dysgeusia"],"offsets":[[2940,2949]],"normalized":[]},{"id":"amyvid_entity_M29","type":"AdverseReaction","text":["pruritis"],"offsets":[[2951,2959]],"normalized":[]},{"id":"amyvid_entity_M30","type":"AdverseReaction","text":["urticaria"],"offsets":[[2961,2970]],"normalized":[]},{"id":"amyvid_entity_M31","type":"AdverseReaction","text":["flushing"],"offsets":[[2976,2984]],"normalized":[]},{"id":"amyvid_entity_M32","type":"AdverseReaction","text":["Radiation risk"],"offsets":[[3131,3145]],"normalized":[]},{"id":"amyvid_entity_M33","type":"AdverseReaction","text":["long-term cumulative radiation exposure"],"offsets":[[3219,3258]],"normalized":[]},{"id":"amyvid_entity_M34","type":"AdverseReaction","text":["long-term cumulative radiation exposure"],"offsets":[[4318,4357]],"normalized":[]},{"id":"amyvid_entity_M35","type":"AdverseReaction","text":["Long-term cumulative radiation 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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. \n\n\n\n A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days. \n\n\n\n Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.\n\n\n\n Table 1: Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group \n\n\n\n\n Adverse Reaction Crofelemer 125 mg BID*N = 229n (%) PlaceboN = 274n (%) \n Upper respiratory tract infection 13 (5.7) 4 (1.5) \n Bronchitis 9 (3.9) 0 \n Cough 8 (3.5) 3 (1.1) \n Flatulence 7 (3.1) 3 (1.1) \n Increased bilirubin 7 (3.1) 3 (1.1) \n Nausea 6 (2.6) 4 (1.5) \n Back pain 6 (2.6) 4 (1.5) \n Arthralgia 6 (2.6) 0 \n Urinary tract infection 5 (2.2) 2 (0.7) \n Nasopharyngitis 5 (2.2) 2 (0.7) \n Musculoskeletal pain 5 (2.2) 1 (0.4) \n Hemorrhoids 5 (2.2) 0 \n Giardiasis 5 (2.2) 0 \n Anxiety 5 (2.2) 1 (0.4) \n Increased alanine aminotransferase 5 (2.2) 3 (1.1) \n Abdominal distension 5 (2.2) 1 (0.4) \n * Twice daily \n Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.\n \n\n Adverse reactions were similar in patients who received doses greater than 250 mg daily.\n\n\n\n EXCERPT: Most common adverse reactions (incidence >= 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-508-0024 or www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \n"],"offsets":[[0,3164]]},{"id":"fulyzaq_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n\n\n 5. 1 Risks of Treatment in Patients with Infectious Diarrhea \n\n\n\n If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.\n\n\n\n EXCERPT: Rule out infectious etiologies of diarrhea before starting crofelemer. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. ( 5.1 )\n"],"offsets":[[3165,3952]]}],"string":"[\n {\n \"id\": \"fulyzaq_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n 6.1 Clinical Trials Experience \\n\\n\\n\\n 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. \\n\\n\\n\\n A total of 696 HIV-positive patients in three placebo-controlled trials received FULYZAQ for a mean duration of 78 days. Of the total population across the three trials, 229 patients received a dose of 125 mg twice a day for a mean duration of 141 days, 69 patients received a dose of 250 mg twice a day for a mean duration of 139 days, 102 patients received a dose of 250 mg four times a day for a mean duration of 14 days, 54 patients received a dose of 500 mg twice a day for a mean duration of 146 days, and 242 patients received a dose of 500 mg four times a day for a mean duration of 14 days. \\n\\n\\n\\n Adverse reactions for FULYZAQ that occurred in at least 2% of patients and at a higher incidence than placebo are provided in Table 1.\\n\\n\\n\\n Table 1: Adverse Reactions Occurring in at Least 2% of Patients in the 125 mg Twice Daily Group \\n\\n\\n\\n\\n Adverse Reaction Crofelemer 125 mg BID*N = 229n (%) PlaceboN = 274n (%) \\n Upper respiratory tract infection 13 (5.7) 4 (1.5) \\n Bronchitis 9 (3.9) 0 \\n Cough 8 (3.5) 3 (1.1) \\n Flatulence 7 (3.1) 3 (1.1) \\n Increased bilirubin 7 (3.1) 3 (1.1) \\n Nausea 6 (2.6) 4 (1.5) \\n Back pain 6 (2.6) 4 (1.5) \\n Arthralgia 6 (2.6) 0 \\n Urinary tract infection 5 (2.2) 2 (0.7) \\n Nasopharyngitis 5 (2.2) 2 (0.7) \\n Musculoskeletal pain 5 (2.2) 1 (0.4) \\n Hemorrhoids 5 (2.2) 0 \\n Giardiasis 5 (2.2) 0 \\n Anxiety 5 (2.2) 1 (0.4) \\n Increased alanine aminotransferase 5 (2.2) 3 (1.1) \\n Abdominal distension 5 (2.2) 1 (0.4) \\n * Twice daily \\n Adverse reactions that occurred in between 1% and 2% of patients taking a 250 mg daily dose of FULYZAQ were abdominal pain, acne, increased aspartate aminotransferase, increased conjugated bilirubin, increased unconjugated blood bilirubin, constipation, depression, dermatitis, dizziness, dry mouth, dyspepsia, gastroenteritis, herpes zoster, nephrolithiasis, pain in extremity, pollakiuria, procedural pain, seasonal allergy, sinusitis and decreased white blood cell count.\\n \\n\\n Adverse reactions were similar in patients who received doses greater than 250 mg daily.\\n\\n\\n\\n EXCERPT: Most common adverse reactions (incidence >= 3%) are upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin. ( 6 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-508-0024 or www.Salix.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch \\n\"\n ],\n \"offsets\": [\n [\n 0,\n 3164\n ]\n ]\n },\n {\n \"id\": \"fulyzaq_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n\\n\\n 5. 1 Risks of Treatment in Patients with Infectious Diarrhea \\n\\n\\n\\n If infectious etiologies are not considered, and FULYZAQ is initiated based on a presumptive diagnosis of non-infectious diarrhea, then there is a risk that patients with infectious etiologies will not receive the appropriate treatments, and their disease may worsen. Before starting FULYZAQ, rule out infectious etiologies of diarrhea. FULYZAQ is not indicated for the treatment of infectious diarrhea.\\n\\n\\n\\n EXCERPT: Rule out infectious etiologies of diarrhea before starting crofelemer. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. 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headache (6.1) \n To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\n \n\n \n\n 6.1 Clinical Trials Experience\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\n\n\n\n Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)] . Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.\n\n\n\n The majority of the most common adverse reactions presented inTable 2occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.\n\n\n\n Table 2: Adverse Reactions Reported in >=2% of Patients on OTEZLA 30 mg Twice Daily and >=1% Than That Observed in Patients on Placebo for up to Day 112 (Week 16) \n a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. \n b Of the reported adverse drug reactions none were serious. \n c n (%) indicates number of patients and percent. \n \n Placebo OTEZLA 30 mg BID \n Preferred Term Day 1 to 5(N=495)n (%) c Day 6 to Day 112(N=490)n (%) Day 1 to 5(N=497)n (%) Day 6 to Day 112(N=493)n (%) \n Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7) \n Nausea a 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9) \n Headache a 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9) \n Upper respiratory tractinfection b 3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9) \n Vomiting a 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2) \n Nasopharyngitis b 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6) \n Abdominal pain upper b 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0) \n Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash*1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.\n \n\n Psoriasis Clinical Trials The safety of OTEZLA (r) was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.\n\n\n\n Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.\n\n\n\n Table 3: Adverse Reactions Reported in >=1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo; up to Day 112 (Week 16) \n * Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. \n \n Preferred Term Placebo (N=506)n (%) OTEZLA 30 mg BID (N=920)n (%) \n Diarrhea 32 (6) 160 (17) \n Nausea 35 (7) 155 (17) \n Upper respiratory tract infection 31 (6) 84 (9) \n Tension headache 21 (4) 75 (8) \n Headache 19 (4) 55 (6) \n Abdominal pain* 11 (2) 39 (4) \n Vomiting 8 (2) 35 (4) \n Fatigue 9 (2) 29 (3) \n Dyspepsia 6 (1) 29 (3) \n Decrease appetite 5 (1) 26 (3) \n Insomnia 4 (1) 21 (2) \n Back pain 4 (1) 20 (2) \n Migraine 5 (1) 19 (2) \n Frequent bowel movements 1 (0) 17 (2) \n Depression 2 (0) 12 (1) \n Bronchitis 2 (0) 12 (1) \n Tooth abscess 0 (0) 10 (1) \n Folliculitis 0 (0) 9 (1) \n Sinus headache 0 (0) 9 (1) \n Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.\n"],"offsets":[[0,7396]]},{"id":"otezla_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS\n\n EXCERPT: * Depression : Advise patients, their caregivers, and families to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes and if such changes occur to contact their healthcare provider. Carefully weigh risks and benefits of treatment with OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior. (5.1) \n * Weight Decrease : Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.2) \n * Drug Interactions : Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.3,7.1) \n \n 5.1 Depression\n\n Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.\n\n\n\n Psoriatic arthritis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.\n\n\n\n Psoriasis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.\n\n\n\n 5.2 Weight Decrease\n\n During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [ see Adverse Reactions (6.1) ].\n\n\n\n During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of >=10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. \n\n\n\n Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.\n\n\n\n 5.3 Drug Interactions\n\n Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. Therefore, the use of cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) with OTEZLA is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].\n"],"offsets":[[7397,11868]]}],"string":"[\n {\n \"id\": \"otezla_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS\\n\\n EXCERPT: * Psoriatic Arthritis : The most common adverse reactions (>=5%) are diarrhea, nausea, and headache (6.1) \\n * Psoriasis : The most common adverse reactions (>=5%) are diarrhea, nausea, upper respiratory tract infection, and headache, including tension headache (6.1) \\n To report SUSPECTED ADVERSE REACTIONS, contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch\\n \\n\\n \\n\\n 6.1 Clinical Trials Experience\\n\\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.\\n\\n\\n\\n Psoriatic Arthritis Clinical Trials OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials [Studies PsA-1, PsA-2, and PsA-3] of similar design in adult patients with active psoriatic arthritis [see Clinical Studies (14.1)] . Across the 3 studies, there were 1493 patients randomized equally to placebo, OTEZLA 20 mg twice daily or OTEZLA 30 mg twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Placebo patients whose tender and swollen joint counts had not improved by at least 20% were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily at week 16 while OTEZLA patients remained on their initial treatment. Patients ranged in age from 18 to 83 years, with an overall median age of 51 years.\\n\\n\\n\\n The majority of the most common adverse reactions presented inTable 2occurred within the first 2 weeks of treatment and tended to resolve over time with continued dosing. Diarrhea, headache, and nausea were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for patients taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%). The proportion of patients with psoriatic arthritis who discontinued treatment due to any adverse reaction was 4.6% for patients taking OTEZLA 30 mg twice daily and 1.2% for placebo-treated patients.\\n\\n\\n\\n Table 2: Adverse Reactions Reported in >=2% of Patients on OTEZLA 30 mg Twice Daily and >=1% Than That Observed in Patients on Placebo for up to Day 112 (Week 16) \\n a Of the reported gastrointestinal adverse reactions, 1 subject experienced a serious adverse reaction of nausea and vomiting in OTEZLA 30 mg twice daily; 1 subject treated with OTEZLA 20 mg twice daily experienced a serious adverse reaction of diarrhea; 1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction of headache. \\n b Of the reported adverse drug reactions none were serious. \\n c n (%) indicates number of patients and percent. \\n \\n Placebo OTEZLA 30 mg BID \\n Preferred Term Day 1 to 5(N=495)n (%) c Day 6 to Day 112(N=490)n (%) Day 1 to 5(N=497)n (%) Day 6 to Day 112(N=493)n (%) \\n Diarrhea a 6 ( 1.2) 8 ( 1.6) 46 ( 9.3) 38 ( 7.7) \\n Nausea a 7 ( 1.4) 15 ( 3.1) 37 ( 7.4) 44 ( 8.9) \\n Headache a 9 ( 1.8) 11 ( 2.2) 24 ( 4.8) 29 ( 5.9) \\n Upper respiratory tractinfection b 3 ( 0.6) 9 ( 1.8) 3 ( 0.6) 19 ( 3.9) \\n Vomiting a 2 ( 0.4) 2 ( 0.4) 4 ( 0.8) 16 ( 3.2) \\n Nasopharyngitis b 1 ( 0.2) 8 ( 1.6) 1 ( 0.2) 13 ( 2.6) \\n Abdominal pain upper b 0 ( 0.0) 1 ( 0.2) 3 ( 0.6) 10 ( 2.0) \\n Other adverse reactions reported in patients on OTEZLA in clinical studies including extension studies: Immune system disorders: Hypersensitivity Investigations: Weight decrease Gastrointestinal Disorders: Frequent bowel movement, gastroesophageal reflux disease, dyspepsia Metabolism and Nutrition Disorders: Decreased appetite* Nervous System Disorders: Migraine Respiratory, Thoracic, and Mediastinal Disorders: Cough Skin and Subcutaneous Tissue Disorders: Rash*1 patient treated with OTEZLA 30 mg twice daily experienced a serious adverse reaction.\\n \\n\\n Psoriasis Clinical Trials The safety of OTEZLA (r) was assessed in 1426 subjects in 3 randomized, double-blind, placebo-controlled trials in adult subjects with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy. Subjects were randomized to receive OTEZLA 30 mg twice daily or placebo twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1) ]. Subjects ranged in age from 18 to 83 years, with an overall median age of 46 years.\\n\\n\\n\\n Diarrhea, nausea, and upper respiratory tract infection were the most commonly reported adverse reactions. The most common adverse reactions leading to discontinuation for subjects taking OTEZLA were nausea (1.6%), diarrhea (1.0%), and headache (0.8%). The proportion of subjects with psoriasis who discontinued treatment due to any adverse reaction was 6.1% for subjects treated with OTEZLA 30 mg twice daily and 4.1% for placebo-treated subjects.\\n\\n\\n\\n Table 3: Adverse Reactions Reported in >=1% of Subjects on OTEZLA and With Greater Frequency Than in Subjects on Placebo; up to Day 112 (Week 16) \\n * Two subjects treated with OTEZLA experienced serious adverse reaction of abdominal pain. \\n \\n Preferred Term Placebo (N=506)n (%) OTEZLA 30 mg BID (N=920)n (%) \\n Diarrhea 32 (6) 160 (17) \\n Nausea 35 (7) 155 (17) \\n Upper respiratory tract infection 31 (6) 84 (9) \\n Tension headache 21 (4) 75 (8) \\n Headache 19 (4) 55 (6) \\n Abdominal pain* 11 (2) 39 (4) \\n Vomiting 8 (2) 35 (4) \\n Fatigue 9 (2) 29 (3) \\n Dyspepsia 6 (1) 29 (3) \\n Decrease appetite 5 (1) 26 (3) \\n Insomnia 4 (1) 21 (2) \\n Back pain 4 (1) 20 (2) \\n Migraine 5 (1) 19 (2) \\n Frequent bowel movements 1 (0) 17 (2) \\n Depression 2 (0) 12 (1) \\n Bronchitis 2 (0) 12 (1) \\n Tooth abscess 0 (0) 10 (1) \\n Folliculitis 0 (0) 9 (1) \\n Sinus headache 0 (0) 9 (1) \\n Severe worsening of psoriasis (rebound) occurred in 0.3% (4/1184) subjects following discontinuation of treatment with OTEZLA.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 7396\n ]\n ]\n },\n {\n \"id\": \"otezla_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS\\n\\n EXCERPT: * Depression : Advise patients, their caregivers, and families to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes and if such changes occur to contact their healthcare provider. Carefully weigh risks and benefits of treatment with OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior. (5.1) \\n * Weight Decrease : Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss and consider discontinuation of OTEZLA (5.2) \\n * Drug Interactions : Use with strong cytochrome P450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended because loss of efficacy may occur (5.3,7.1) \\n \\n 5.1 Depression\\n\\n Treatment with OTEZLA is associated with an increase in adverse reactions of depression. Before using OTEZLA in patients with a history of depression and/or suicidal thoughts or behavior prescribers should carefully weigh the risks and benefits of treatment with OTEZLA in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with OTEZLA if such events occur.\\n\\n\\n\\n Psoriatic arthritis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.0% (10/998) of subjects treated with OTEZLA reported depression or depressed mood compared to 0.8% (4/495) treated with placebo. During the clinical trials, 0.3% (4/1441) of subjects treated with OTEZLA discontinued treatment due to depression or depressed mood compared with none in placebo treated subjects (0/495). Depression was reported as serious in 0.2% (3/1441) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/495). Instances of suicidal ideation and behavior have been observed in 0.2% (3/1441) of subjects while receiving OTEZLA, compared to none in placebo treated subjects (0/495). In the clinical trials, 2 subjects who received placebo committed suicide compared to none in OTEZLA-treated subjects.\\n\\n\\n\\n Psoriasis : During the 0 to 16 week placebo-controlled period of the 3 controlled clinical trials, 1.3% (12/920) of subjects treated with OTEZLA reported depression compared to 0.4% (2/506) treated with placebo. During the clinical trials, 0.1% (1/1308) of subjects treated with OTEZLA discontinued treatment due to depression compared with none in placebo-treated subjects(0/506). Depression was reported as serious in 0.1% (1/1308) of subjects exposed to OTEZLA, compared to none in placebo-treated subjects (0/506). Instances of suicidal behavior have been observed in 0.1% (1/1308) of subjects while receiving OTEZLA, compared to 0.2% (1/506) in placebo-treated subjects. In the clinical trials, one subject treated with OTEZLA attempted suicide while one who received placebo committed suicide.\\n\\n\\n\\n 5.2 Weight Decrease\\n\\n During the controlled period of the studies in psoriatic arthritis (PsA), weight decrease between 5%-10% of body weight was reported in 10% (49/497) of subjects treated with OTEZLA 30 mg twice daily compared to 3.3% (16/495) treated with placebo [ see Adverse Reactions (6.1) ].\\n\\n\\n\\n During the controlled period of the trials in psoriasis, weight decrease between 5%-10% of body weight occurred in 12% (96/784) of subjects treated with OTEZLA compared to 5% (19/382) treated with placebo. Weight decrease of >=10% of body weight occurred in 2% (16/784) of subjects treated with OTEZLA 30 mg twice daily compared to 1% (3/382) subjects treated with placebo. \\n\\n\\n\\n Patients treated with OTEZLA should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of OTEZLA should be considered.\\n\\n\\n\\n 5.3 Drug Interactions\\n\\n Co-administration of strong cytochrome P450 enzyme inducer, rifampin, resulted in a reduction of systemic exposure of apremilast, which may result in a loss of efficacy of OTEZLA. 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( 6 )\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Zylera Pharmaceuticals, LLC. at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \n\n\n\n \n\n 6.1 Clinical Trials Experience \n\n 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 clinical practice.\n\n\n\n The rates of adverse reactions below were derived from two randomized, multi-center, vehicle-controlled clinical trials and one open-label study in subjects with head lice infestation.\n\n\n\n Skin, scalp, and ocular irritation were monitored in the clinical trials. All subjects were queried about the presence of skin and scalp symptoms; the results are presented in Table 2.\n\n\n\n \n\n\n\n Table 2: Monitored Adverse Reactions - Application Site Symptoms \n Event ULESFIA (r) Lotion Vehicle \n Application site Irritation 2% (11/478) 1% (2/336) \n Application site anesthesia &hypoesthesia 2% (10/478) 0% (0/336) \n Pain 1% (5/478) 0% (1/336) \n The subset of subjects who did not have pruritus, erythema, edema or pyoderma of skin and scalp, or ocular irritation prior to treatment were assessed for these signs and symptoms after treatment; the results are presented in Table 3.\n \n\n \n\n\n\n Table 3: Monitored Adverse Reactions - Pruritus, Erythema, Pyoderma and Ocular Irritation with Onset After Treatment \n Signs/Symptoms ULESFIA (r) Lotion Vehicle \n Pruritus 12% (14/116) 4% (3/67) \n Erythema 10% (32/309) 9% (19/217) \n Pyoderma 7% (22/308) 4% (10/230) \n Ocular irritation 6% (26/428) 1% (3/313) \n Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence: application site dryness, application site excoriation, paraesthesia, application site dermatitis, excoriation, thermal burn, dandruff, erythema, rash, and skin exfoliation.\n"],"offsets":[[0,2408]]},{"id":"ulesfia_section_S2","type":"warnings and precautions","text":[" 5 WARNINGS AND PRECAUTIONS \n\n\n\n EXCERPT: * Neonatal toxicity: Risk of gasping syndrome if benzyl alcohol is used in neonates. ( 5.1 ) \n * Eye irritation: Avoid eye exposure. Flush immediately with water if ULESFIA (r) Lotion comes into contact with eyes. ( 5.2 ) \n * Contact dermatitis: May occur with ULESFIA (r) Lotion. ( 5.3 ) \n * Use in children: ULESFIA (r) Lotion should only be used on children under the direct supervision of an adult. Keep out of reach of children. ( 5.4 ) \n \n \n\n 5. 1 Neonatal Toxicity \n\n\n\n Intravenous administration of products containing benzyl alcohol has been associated with neonatal gasping syndrome consisting of severe metabolic acidosis, gasping respirations, progressive hypotension, seizures, central nervous system depression, intraventricular hemorrhage, and death in preterm, low birth weight infants. Neonates (i.e. patients less than 1 month of age or preterm infants with a corrected age of less than 44 weeks) could be at risk for gasping syndrome if treated with ULESFIA (r) Lotion [see Use in Specific Populations ( 8.4 )] . \n\n\n\n \n\n\n\n 5.2 Eye Irritation \n\n\n\n Avoid eye exposure. ULESFIA (r) Lotion may cause eye irritation. If ULESFIA (r) Lotion comes in contact with the eyes, flush them immediately with water. If irritation persists, consult a physician.\n\n\n\n \n\n\n\n 5. 3 Contact Dermatitis \n\n\n\n ULESFIA (r) Lotion may cause allergic or irritant dermatitis.\n\n\n\n \n\n\n\n 5.4 Use in Children \n\n\n\n ULESFIA (r) Lotion should only be used on children (6 months of age and older) under the direct supervision of an adult. Keep out of reach of children.\n"],"offsets":[[2409,4215]]}],"string":"[\n {\n \"id\": \"ulesfia_section_S1\",\n \"type\": \"adverse reactions\",\n \"text\": [\n \" 6 ADVERSE REACTIONS \\n\\n EXCERPT: Most common adverse reactions (> 1% and more common than with placebo): ocular irritation, application site irritation, and application site anesthesia and hypoesthesia. ( 6 )\\n\\n\\n\\n To report SUSPECTED ADVERSE REACTIONS, contact Zylera Pharmaceuticals, LLC. at 1-866-416-9637 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. \\n\\n\\n\\n \\n\\n 6.1 Clinical Trials Experience \\n\\n 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 clinical practice.\\n\\n\\n\\n The rates of adverse reactions below were derived from two randomized, multi-center, vehicle-controlled clinical trials and one open-label study in subjects with head lice infestation.\\n\\n\\n\\n Skin, scalp, and ocular irritation were monitored in the clinical trials. All subjects were queried about the presence of skin and scalp symptoms; the results are presented in Table 2.\\n\\n\\n\\n \\n\\n\\n\\n Table 2: Monitored Adverse Reactions - Application Site Symptoms \\n Event ULESFIA (r) Lotion Vehicle \\n Application site Irritation 2% (11/478) 1% (2/336) \\n Application site anesthesia &hypoesthesia 2% (10/478) 0% (0/336) \\n Pain 1% (5/478) 0% (1/336) \\n The subset of subjects who did not have pruritus, erythema, edema or pyoderma of skin and scalp, or ocular irritation prior to treatment were assessed for these signs and symptoms after treatment; the results are presented in Table 3.\\n \\n\\n \\n\\n\\n\\n Table 3: Monitored Adverse Reactions - Pruritus, Erythema, Pyoderma and Ocular Irritation with Onset After Treatment \\n Signs/Symptoms ULESFIA (r) Lotion Vehicle \\n Pruritus 12% (14/116) 4% (3/67) \\n Erythema 10% (32/309) 9% (19/217) \\n Pyoderma 7% (22/308) 4% (10/230) \\n Ocular irritation 6% (26/428) 1% (3/313) \\n Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence: application site dryness, application site excoriation, paraesthesia, application site dermatitis, excoriation, thermal burn, dandruff, erythema, rash, and skin exfoliation.\\n\"\n ],\n \"offsets\": [\n [\n 0,\n 2408\n ]\n ]\n },\n {\n \"id\": \"ulesfia_section_S2\",\n \"type\": \"warnings and precautions\",\n \"text\": [\n \" 5 WARNINGS AND PRECAUTIONS \\n\\n\\n\\n EXCERPT: * Neonatal toxicity: Risk of gasping syndrome if benzyl alcohol is used in neonates. ( 5.1 ) \\n * Eye irritation: Avoid eye exposure. Flush immediately with water if ULESFIA (r) Lotion comes into contact with eyes. ( 5.2 ) \\n * Contact dermatitis: May occur with ULESFIA (r) Lotion. ( 5.3 ) \\n * Use in children: ULESFIA (r) Lotion should only be used on children under the direct supervision of an adult. Keep out of reach of children. ( 5.4 ) \\n \\n \\n\\n 5. 1 Neonatal Toxicity \\n\\n\\n\\n Intravenous administration of products containing benzyl alcohol has been associated with neonatal gasping syndrome consisting of severe metabolic acidosis, gasping respirations, progressive hypotension, seizures, central nervous system depression, intraventricular hemorrhage, and death in preterm, low birth weight infants. Neonates (i.e. patients less than 1 month of age or preterm infants with a corrected age of less than 44 weeks) could be at risk for gasping syndrome if treated with ULESFIA (r) Lotion [see Use in Specific Populations ( 8.4 )] . \\n\\n\\n\\n \\n\\n\\n\\n 5.2 Eye Irritation \\n\\n\\n\\n Avoid eye exposure. ULESFIA (r) Lotion may cause eye irritation. If ULESFIA (r) Lotion comes in contact with the eyes, flush them immediately with water. If irritation persists, consult a physician.\\n\\n\\n\\n \\n\\n\\n\\n 5. 3 Contact Dermatitis \\n\\n\\n\\n ULESFIA (r) Lotion may cause allergic or irritant dermatitis.\\n\\n\\n\\n \\n\\n\\n\\n 5.4 Use in Children \\n\\n\\n\\n ULESFIA (r) Lotion should only be used on children (6 months of age and older) under the direct supervision of an adult. 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id stringlengths 1 3 | document_id stringlengths 4 9 | passages list | entities list | events list | coreferences list | relations list |
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0 | vizamyl | [
{
"id": "vizamyl_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Most commonly reported adverse reactions were flushing (2%), headache (1%), increased blood pressure (2%), nausea (1%), and dizziness (1%).\n\n\n\n To report SUSPECTED ADVERSE REACTIONS,... | [
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1 | horizant | [
{
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"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Somnolence/sedation and dizziness [see Warnings and Precautions ( 5.... | [
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"sedation"
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"... |
2 | pristiq | [
{
"id": "pristiq_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label.\n\n\n\n * Hypersensitivity [see Contraindications (4) ] \n * Suicidal Thoughts and Behaviors i... | [
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"id": "pristiq_entity_M2",
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"text": [
"Suicidal Thoughts"
],
... | [] | [] | [
{
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{
"id": "pristiq_relation_RL2",
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"arg2_id": "M106",
"normalized": []
},
{
"id": "pristiq_relation_RL3",
"type": "Ne... |
3 | beleodaq | [
{
"id": "beleodaq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are described in more detail in other sections of the prescribing information.\n\n\n\n * Hematologic Toxicity [see Warnings and Precautions ( 5.1 )] \... | [
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{
"id": "beleodaq_entity_M2",
"type": "AdverseReaction",
"text": [
"Infection"
],
... | [] | [] | [
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"id": "beleodaq_relation_RL1",
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"arg1_id": "M50",
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4 | picato | [
{
"id": "picato_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n \n\n\n\n The following serious adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n \n\n\n\n * Ophthalmic Adverse Reaction [see Warnings and Precautio... | [
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"Ophthalmic Adverse Reaction"
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"id": "picato_entity_M2",
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"Hypersensitivity Re... | [] | [] | [
{
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"arg2_id": "M67",
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"arg1_id": "M61",
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{
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5 | dysport | [
{
"id": "dysport_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed below and elsewhere in labeling:\n\n\n\n * Distant Spread of Toxin Effect [seeBoxed Warning] \n * Lack of Interchangeability between Botulinum... | [
{
"id": "dysport_entity_M1",
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"Distant Spread of Toxin Effect"
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"id": "dysport_entity_M2",
"type": "AdverseReaction",
"text": [
"Spread of Effe... | [] | [] | [
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"id": "dysport_relation_RL3",
"type": "Effec... |
6 | xtandi | [
{
"id": "xtandi_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following is discussed in more detail in other sections of the labeling:\n\n\n\n * Seizure [see Warnings and Precautions ( 5.1 )] \n EXCERPT: The most common adverse reactions (>= 1... | [
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"id": "xtandi_entity_M2",
"type": "AdverseReaction",
"text": [
"asthenia"
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... | [] | [] | [
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"id": "xtandi_relation_RL1",
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{
"id": "xtandi_relation_RL3",
"type": "Effect... |
7 | stendra | [
{
"id": "stendra_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Most common adverse reactions (greater than or equal to 2%) include headache, flushing, nasal congestion, nasopharyngitis, and back pain (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIO... | [
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"id": "stendra_entity_M2",
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"flushing"
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... | [] | [] | [
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{
"id": "stendra_relation_RL3",
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8 | potiga | [
{
"id": "potiga_section_S1",
"type": "adverse reactions",
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" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Retinal abnormalities and potential vision loss [see Warnings and Prec... | [
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{
"id": "potiga_entity_M2",
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"potential"
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{
"id": "potiga_relation_RL3",
"type":... |
9 | dalvance | [
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"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of a... | [
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"id": "dalvance_relation_RL3",
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10 | promacta | [
{
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" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions associated with PROMACTA are described in other sections.\n\n\n\n * Hepatic Decompensation in Patients with Chronic Hepatitis C [see Warnings and Precautio... | [
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"Hepatotoxicity"
... | [] | [] | [
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11 | arcapta | [
{
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"text": [
" 6 ADVERSE REACTIONS \n\n L ong - acting beta 2 -adrenergic agonists , such as A RCAPTA NEOHALER , increase the risk of asthma-related death . ARCAPTA NEOHALER is not indicated fo... | [
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1... | [] | [] | [
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12 | onfi | [
{
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" 6 ADVERSE REACTIONS \n\n Clinically significant adverse reactions that appear in other sections of the labeling include the following:\n\n\n\n * Somnolence or Sedation [see Warnings and Precautions ( 5.1 )] \n * Potent... | [
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13 | coartem | [
{
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"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n EXCERPT: The most common adverse reactions in adults (>30%) are headache, anorexia, dizziness, asthenia, arthralgia and myalgia. The most common adverse reactions in children (>12%) are pyr... | [
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... | [] | [] | [
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{
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"type": "Hypothetical",
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"arg2_id": "M126",
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}
] |
14 | entereg | [
{
"id": "entereg_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction (incidence >=1.5%) occurring with a higher frequency than placebo among ENTEREG-treated patients undergoing surgeries that included a bowel resection was d... | [
{
"id": "entereg_entity_M1",
"type": "AdverseReaction",
"text": [
"dyspepsia"
],
"offsets": [
[
225,
234
]
],
"normalized": []
},
{
"id": "entereg_entity_M2",
"type": "AdverseReaction",
"text": [
"dyspepsia"
],
"offsets": [
... | [] | [] | [
{
"id": "entereg_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M4",
"arg2_id": "M3",
"normalized": []
},
{
"id": "entereg_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M6",
"arg2_id": "M5",
"normalized": []
},
{
"id": "entereg_relation_RL3",
"type": ... |
15 | choline | [
{
"id": "choline_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n Exclusive of an uncommon, mild injection site reaction, no adverse reactions to 11 C-choline have been reported.\n\n\n\n EXCERPT: Exclusive of an uncommon, mild injection site re... | [
{
"id": "choline_entity_M1",
"type": "Severity",
"text": [
"mild"
],
"offsets": [
[
68,
72
]
],
"normalized": []
},
{
"id": "choline_entity_M2",
"type": "AdverseReaction",
"text": [
"injection site reaction"
],
"offsets": [
... | [] | [] | [
{
"id": "choline_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "choline_relation_RL2",
"type": "Effect",
"arg1_id": "M4",
"arg2_id": "M3",
"normalized": []
},
{
"id": "choline_relation_RL3",
"type": "Hypothetica... |
16 | fanapt | [
{
"id": "fanapt_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Commonly observed adverse reactions (incidence >=5% and 2-fold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycar... | [
{
"id": "fanapt_entity_M1",
"type": "AdverseReaction",
"text": [
"dizziness"
],
"offsets": [
[
133,
142
]
],
"normalized": []
},
{
"id": "fanapt_entity_M2",
"type": "AdverseReaction",
"text": [
"dry mouth"
],
"offsets": [
... | [] | [] | [
{
"id": "fanapt_relation_RL1",
"type": "Effect",
"arg1_id": "M64",
"arg2_id": "M65",
"normalized": []
},
{
"id": "fanapt_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M164",
"arg2_id": "M163",
"normalized": []
},
{
"id": "fanapt_relation_RL3",
"type": "Hy... |
17 | sirturo | [
{
"id": "sirturo_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the labeling:\n\n\n\n * Increased mortality [see Warnings and Precautions (5.1) ] \n * QT Prolongation [see Warnings and Preca... | [
{
"id": "sirturo_entity_M1",
"type": "AdverseReaction",
"text": [
"Increased mortality"
],
"offsets": [
[
115,
134
]
],
"normalized": []
},
{
"id": "sirturo_entity_M2",
"type": "AdverseReaction",
"text": [
"QT Prolongation"
],
... | [] | [] | [
{
"id": "sirturo_relation_RL1",
"type": "Effect",
"arg1_id": "M18",
"arg2_id": "M19",
"normalized": []
},
{
"id": "sirturo_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M22",
"arg2_id": "M23",
"normalized": []
},
{
"id": "sirturo_relation_RL3",
"type": "N... |
18 | blincyto | [
{
"id": "blincyto_section_S1",
"type": "adverse reactions",
"text": [
" 6. ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label: \n\n\n\n * Cytokine Release Syndrome [see Warnings and Precautions ( 5.1 )] \n * Neurological... | [
{
"id": "blincyto_entity_M1",
"type": "AdverseReaction",
"text": [
"Cytokine Release Syndrome"
],
"offsets": [
[
135,
160
]
],
"normalized": []
},
{
"id": "blincyto_entity_M2",
"type": "AdverseReaction",
"text": [
"Neurological Toxi... | [] | [] | [
{
"id": "blincyto_relation_RL1",
"type": "Negated",
"arg1_id": "M45",
"arg2_id": "M44",
"normalized": []
},
{
"id": "blincyto_relation_RL2",
"type": "Effect",
"arg1_id": "M144",
"arg2_id": "M148",
"normalized": []
},
{
"id": "blincyto_relation_RL3",
"type": "E... |
19 | adcetris | [
{
"id": "adcetris_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information:\n\n\n\n * Peripheral Neuropathy [see Warnings and Precautions ( 5.1 ... | [
{
"id": "adcetris_entity_M1",
"type": "AdverseReaction",
"text": [
"Peripheral Neuropathy"
],
"offsets": [
[
156,
177
]
],
"normalized": []
},
{
"id": "adcetris_entity_M2",
"type": "AdverseReaction",
"text": [
"Anaphylaxis"
],
... | [] | [] | [
{
"id": "adcetris_relation_RL1",
"type": "Effect",
"arg1_id": "M6",
"arg2_id": "M5",
"normalized": []
},
{
"id": "adcetris_relation_RL2",
"type": "Effect",
"arg1_id": "M15",
"arg2_id": "M14",
"normalized": []
},
{
"id": "adcetris_relation_RL3",
"type": "Effect... |
20 | tivicay | [
{
"id": "tivicay_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse drug reactions (adverse events assessed as causally related by the investigator or ADRs) are discussed in other sections of the labeling:\n\n\n\n * Hypersensitivity reactions... | [
{
"id": "tivicay_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity"
],
"offsets": [
[
196,
212
]
],
"normalized": []
},
{
"id": "tivicay_entity_M2",
"type": "AdverseReaction",
"text": [
"Fat Redistribution"
],
... | [] | [] | [
{
"id": "tivicay_relation_RL1",
"type": "Effect",
"arg1_id": "M6",
"arg2_id": "M4",
"normalized": []
},
{
"id": "tivicay_relation_RL2",
"type": "Effect",
"arg1_id": "M6",
"arg2_id": "M5",
"normalized": []
},
{
"id": "tivicay_relation_RL3",
"type": "Effect",
... |
21 | eovist | [
{
"id": "eovist_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactionsare discussed elsewhere in the labeling:\n\n\n\n * Nephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions ( 5.1 )] \n * Hyp... | [
{
"id": "eovist_entity_M1",
"type": "AdverseReaction",
"text": [
"Nephrogenic systemic fibrosis"
],
"offsets": [
[
116,
145
]
],
"normalized": []
},
{
"id": "eovist_entity_M2",
"type": "AdverseReaction",
"text": [
"NSF"
],
"... | [] | [] | [
{
"id": "eovist_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M75",
"arg2_id": "M74",
"normalized": []
},
{
"id": "eovist_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M78",
"arg2_id": "M77",
"normalized": []
},
{
"id": "eovist_relation_RL3",
"type":... |
22 | edarbi | [
{
"id": "edarbi_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction in adults was diarrhea (2%). (6.1)\n\n\n\n To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC at 1-866-516-4950 or FDA at 1-800-FDA... | [
{
"id": "edarbi_entity_M1",
"type": "AdverseReaction",
"text": [
"diarrhea"
],
"offsets": [
[
85,
93
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10012727"
}
]
},
{
"id": "edarbi_entity_M2",
... | [] | [] | [
{
"id": "edarbi_relation_RL1",
"type": "Effect",
"arg1_id": "M14",
"arg2_id": "M12",
"normalized": []
},
{
"id": "edarbi_relation_RL2",
"type": "Effect",
"arg1_id": "M14",
"arg2_id": "M13",
"normalized": []
},
{
"id": "edarbi_relation_RL3",
"type": "Effect",
... |
23 | xiaflex | [
{
"id": "xiaflex_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions in patients with Dupuytren's contracture are discussed in greater detail elsewhere in the labeling:\n\n\n\n * Tendon ruptures or other serious injury to the i... | [
{
"id": "xiaflex_entity_M1",
"type": "AdverseReaction",
"text": [
"Tendon ruptures"
],
"offsets": [
[
174,
189
]
],
"normalized": []
},
{
"id": "xiaflex_entity_M2",
"type": "Severity",
"text": [
"serious"
],
"offsets": [
... | [] | [] | [
{
"id": "xiaflex_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "xiaflex_relation_RL2",
"type": "Effect",
"arg1_id": "M7",
"arg2_id": "M6",
"normalized": []
},
{
"id": "xiaflex_relation_RL3",
"type": "Hypothetica... |
24 | duavee | [
{
"id": "duavee_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the label:\n\n\n\n * Cardiovascular Disorders [see Warnings and Precautions (5.2) ] \n * Malignant Neoplasms [... | [
{
"id": "duavee_entity_M1",
"type": "AdverseReaction",
"text": [
"Cardiovascular Disorders"
],
"offsets": [
[
130,
154
]
],
"normalized": []
},
{
"id": "duavee_entity_M2",
"type": "AdverseReaction",
"text": [
"Malignant Neoplasms"
... | [] | [] | [
{
"id": "duavee_relation_RL1",
"type": "Negated",
"arg1_id": "M13",
"arg2_id": "M14",
"normalized": []
},
{
"id": "duavee_relation_RL2",
"type": "Negated",
"arg1_id": "M30",
"arg2_id": "M31",
"normalized": []
},
{
"id": "duavee_relation_RL3",
"type": "Hypothet... |
25 | datscan | [
{
"id": "datscan_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Hypersensitivity and injection site reactions have been reported following DaTscan administration. ( 6.2 ) In clinical trials, the most common adverse reactions, headache, nausea, vertig... | [
{
"id": "datscan_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity"
],
"offsets": [
[
38,
54
]
],
"normalized": []
},
{
"id": "datscan_entity_M2",
"type": "AdverseReaction",
"text": [
"injection site reactions"
... | [] | [] | [] |
26 | ferriprox | [
{
"id": "ferriprox_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * The most common adverse reactions are (incidence >= 5%) chromaturia, nausea, vomiting and abdominal pain, alanine aminotransferase increased, arthralgia and neutropenia. ( 5.1 ,... | [
{
"id": "ferriprox_entity_M1",
"type": "AdverseReaction",
"text": [
"chromaturia"
],
"offsets": [
[
101,
112
]
],
"normalized": []
},
{
"id": "ferriprox_entity_M2",
"type": "AdverseReaction",
"text": [
"nausea"
],
"offsets":... | [] | [] | [
{
"id": "ferriprox_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M112",
"arg2_id": "M111",
"normalized": []
},
{
"id": "ferriprox_relation_RL2",
"type": "Effect",
"arg1_id": "M115",
"arg2_id": "M114",
"normalized": []
},
{
"id": "ferriprox_relation_RL3",
... |
27 | gilenya | [
{
"id": "gilenya_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are described elsewhere in labeling:\n\n\n\n * Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions (5.1)] \n * Infections [see War... | [
{
"id": "gilenya_entity_M1",
"type": "AdverseReaction",
"text": [
"Bradyarrhythmia"
],
"offsets": [
[
115,
130
]
],
"normalized": []
},
{
"id": "gilenya_entity_M2",
"type": "AdverseReaction",
"text": [
"Atrioventricular Blocks"
... | [] | [] | [
{
"id": "gilenya_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M71",
"arg2_id": "M70",
"normalized": []
},
{
"id": "gilenya_relation_RL2",
"type": "Effect",
"arg1_id": "M94",
"arg2_id": "M93",
"normalized": []
},
{
"id": "gilenya_relation_RL3",
"type": "N... |
28 | durezol | [
{
"id": "durezol_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular ca... | [
{
"id": "durezol_entity_M1",
"type": "DrugClass",
"text": [
"ophthalmic steroids"
],
"offsets": [
[
61,
80
]
],
"normalized": []
},
{
"id": "durezol_entity_M2",
"type": "AdverseReaction",
"text": [
"elevated intraocular pressure"
... | [] | [] | [
{
"id": "durezol_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "durezol_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M3",
"arg2_id": "M1",
"normalized": []
},
{
"id": "durezol_relation_RL3",
"type": ... |
29 | cometriq | [
{
"id": "cometriq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the label:\n\n\n\n * Perforations and Fistula [ see Boxed Warning , Warnings and Precautions ( 5.1 ) ] \n * Hemorrhage [ se... | [
{
"id": "cometriq_entity_M1",
"type": "AdverseReaction",
"text": [
"Perforations"
],
"offsets": [
[
112,
124
]
],
"normalized": []
},
{
"id": "cometriq_entity_M2",
"type": "AdverseReaction",
"text": [
"Fistula"
],
"offsets":... | [] | [] | [
{
"id": "cometriq_relation_RL1",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M58",
"normalized": []
},
{
"id": "cometriq_relation_RL2",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M57",
"normalized": []
},
{
"id": "cometriq_relation_RL3",
"type": "Effe... |
30 | zydelig | [
{
"id": "zydelig_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions have been associated with Zydelig in clinical trials and are discussed in greater detail in other sections of the prescribing information.\n\n\n\n * Hepatotox... | [
{
"id": "zydelig_entity_M1",
"type": "AdverseReaction",
"text": [
"Hepatotoxicity"
],
"offsets": [
[
213,
227
]
],
"normalized": []
},
{
"id": "zydelig_entity_M2",
"type": "Severity",
"text": [
"Severe"
],
"offsets": [
... | [] | [] | [
{
"id": "zydelig_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "zydelig_relation_RL2",
"type": "Effect",
"arg1_id": "M4",
"arg2_id": "M2",
"normalized": []
},
{
"id": "zydelig_relation_RL3",
"type": "Effect",
... |
31 | multaq | [
{
"id": "multaq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following safety concerns are described elsewhere in the label:\n\n\n\n * New or worsening heart failure [see Warnings and Precautions (5.4) ] \n * Liver Injury [see Warnings and Precaut... | [
{
"id": "multaq_entity_M1",
"type": "AdverseReaction",
"text": [
"New",
"heart failure"
],
"offsets": [
[
104,
107
],
[
121,
134
]
],
"normalized": []
},
{
"id": "multaq_entity_M2",
"type": "AdverseReaction",... | [] | [] | [
{
"id": "multaq_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M52",
"arg2_id": "M51",
"normalized": []
},
{
"id": "multaq_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M53",
"arg2_id": "M51",
"normalized": []
},
{
"id": "multaq_relation_RL3",
"type":... |
32 | dificid | [
{
"id": "dificid_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%) ( 6 ).\n\n\n\n To report SUS... | [
{
"id": "dificid_entity_M1",
"type": "AdverseReaction",
"text": [
"nausea"
],
"offsets": [
[
76,
82
]
],
"normalized": []
},
{
"id": "dificid_entity_M2",
"type": "AdverseReaction",
"text": [
"vomiting"
],
"offsets": [
... | [] | [] | [] |
33 | zykadia | [
{
"id": "zykadia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Severe or Persistent Gastrointestinal Toxicity [see Warnings and Precautions (5.1... | [
{
"id": "zykadia_entity_M1",
"type": "Severity",
"text": [
"Severe"
],
"offsets": [
[
141,
147
]
],
"normalized": []
},
{
"id": "zykadia_entity_M2",
"type": "Severity",
"text": [
"Persistent"
],
"offsets": [
[
... | [] | [] | [
{
"id": "zykadia_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M1",
"normalized": []
},
{
"id": "zykadia_relation_RL2",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "zykadia_relation_RL3",
"type": "Hypothetica... |
34 | tanzeum | [
{
"id": "tanzeum_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious reactions are described below or elsewhere in the prescribing information:\n\n\n\n * Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)] \n * Acute Pancrea... | [
{
"id": "tanzeum_entity_M1",
"type": "Factor",
"text": [
"Risk"
],
"offsets": [
[
133,
137
]
],
"normalized": []
},
{
"id": "tanzeum_entity_M2",
"type": "AdverseReaction",
"text": [
"Thyroid C-cell Tumors"
],
"offsets": [
... | [] | [] | [
{
"id": "tanzeum_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "tanzeum_relation_RL2",
"type": "Effect",
"arg1_id": "M35",
"arg2_id": "M38",
"normalized": []
},
{
"id": "tanzeum_relation_RL3",
"type": "Eff... |
35 | treanda | [
{
"id": "treanda_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the label.\n\n\n\n * Myelosuppression [see Wa... | [
{
"id": "treanda_entity_M1",
"type": "AdverseReaction",
"text": [
"Myelosuppression"
],
"offsets": [
[
197,
213
]
],
"normalized": []
},
{
"id": "treanda_entity_M2",
"type": "AdverseReaction",
"text": [
"Infections"
],
"offs... | [] | [] | [
{
"id": "treanda_relation_RL1",
"type": "Negated",
"arg1_id": "M74",
"arg2_id": "M72",
"normalized": []
},
{
"id": "treanda_relation_RL2",
"type": "Effect",
"arg1_id": "M75",
"arg2_id": "M73",
"normalized": []
},
{
"id": "treanda_relation_RL3",
"type": "Negate... |
36 | qutenza | [
{
"id": "qutenza_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed elsewhere in the labeling:\n\n\n\n Application-Associated Pain [ see Warnings and Precautions (5.4 )] \n\n\n\n Increase in Blood Pressure [ ... | [
{
"id": "qutenza_entity_M1",
"type": "AdverseReaction",
"text": [
"Application-Associated Pain"
],
"offsets": [
[
112,
139
]
],
"normalized": []
},
{
"id": "qutenza_entity_M2",
"type": "AdverseReaction",
"text": [
"Increase in Blood... | [] | [] | [
{
"id": "qutenza_relation_RL1",
"type": "Effect",
"arg1_id": "M12",
"arg2_id": "M13",
"normalized": []
},
{
"id": "qutenza_relation_RL2",
"type": "Effect",
"arg1_id": "M15",
"arg2_id": "M14",
"normalized": []
},
{
"id": "qutenza_relation_RL3",
"type": "Hypothe... |
37 | ilaris | [
{
"id": "ilaris_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n Three hundred ninety-five patients, including approximately 250 children (aged 2 to 17 years) have been treated with ILARIS in interventional trials in CAPS or SJIA. The most frequently report... | [
{
"id": "ilaris_entity_M1",
"type": "AdverseReaction",
"text": [
"infections"
],
"offsets": [
[
258,
268
]
],
"normalized": []
},
{
"id": "ilaris_entity_M2",
"type": "AdverseReaction",
"text": [
"infections",
"of the upper res... | [] | [] | [
{
"id": "ilaris_relation_RL1",
"type": "Effect",
"arg1_id": "M7",
"arg2_id": "M6",
"normalized": []
},
{
"id": "ilaris_relation_RL2",
"type": "Effect",
"arg1_id": "M8",
"arg2_id": "M3",
"normalized": []
},
{
"id": "ilaris_relation_RL3",
"type": "Effect",
"... |
38 | nulojix | [
{
"id": "nulojix_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions reported with NULOJIX are:\n\n\n\n * PTLD, predominantly CNS PTLD, and other malignancies [see Boxed Warning and Warnings and Precautions (5.1 , 5.3) ]... | [
{
"id": "nulojix_entity_M1",
"type": "AdverseReaction",
"text": [
"PTLD"
],
"offsets": [
[
98,
102
]
],
"normalized": []
},
{
"id": "nulojix_entity_M2",
"type": "AdverseReaction",
"text": [
"CNS PTLD"
],
"offsets": [
[... | [] | [] | [
{
"id": "nulojix_relation_RL1",
"type": "Effect",
"arg1_id": "M5",
"arg2_id": "M4",
"normalized": []
},
{
"id": "nulojix_relation_RL2",
"type": "Negated",
"arg1_id": "M63",
"arg2_id": "M62",
"normalized": []
},
{
"id": "nulojix_relation_RL3",
"type": "Negated"... |
39 | yervoy | [
{
"id": "yervoy_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling.\n\n\n\n * ? Immune-mediated enterocolitis [see Warnings and Precautions (5.1) ] . \n * ? Imm... | [
{
"id": "yervoy_entity_M1",
"type": "AdverseReaction",
"text": [
"Immune-mediated enterocolitis"
],
"offsets": [
[
139,
168
]
],
"normalized": []
},
{
"id": "yervoy_entity_M2",
"type": "AdverseReaction",
"text": [
"Immune-mediated h... | [] | [] | [
{
"id": "yervoy_relation_RL1",
"type": "Effect",
"arg1_id": "M26",
"arg2_id": "M24",
"normalized": []
},
{
"id": "yervoy_relation_RL2",
"type": "Effect",
"arg1_id": "M26",
"arg2_id": "M23",
"normalized": []
},
{
"id": "yervoy_relation_RL3",
"type": "Effect",
... |
40 | jardiance | [
{
"id": "jardiance_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions ( 5.1 )] \n * Impairment in Renal Function [se... | [
{
"id": "jardiance_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypotension"
],
"offsets": [
[
128,
139
]
],
"normalized": []
},
{
"id": "jardiance_entity_M2",
"type": "AdverseReaction",
"text": [
"Impairment in Renal Function"... | [] | [] | [
{
"id": "jardiance_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M48",
"arg2_id": "M47",
"normalized": []
},
{
"id": "jardiance_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M59",
"arg2_id": "M58",
"normalized": []
},
{
"id": "jardiance_relation_RL3",
... |
41 | benlysta | [
{
"id": "benlysta_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials ... | [
{
"id": "benlysta_entity_M1",
"type": "AdverseReaction",
"text": [
"Mortality"
],
"offsets": [
[
423,
432
]
],
"normalized": []
},
{
"id": "benlysta_entity_M2",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[... | [] | [] | [
{
"id": "benlysta_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "benlysta_relation_RL2",
"type": "Effect",
"arg1_id": "M20",
"arg2_id": "M19",
"normalized": []
},
{
"id": "benlysta_relation_RL3",
"type": "Effect... |
42 | bosulif | [
{
"id": "bosulif_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Gastrointestinal toxicity [see Dosage and Administration (2.3) and Warnings and Precau... | [
{
"id": "bosulif_entity_M1",
"type": "AdverseReaction",
"text": [
"Gastrointestinal toxicity"
],
"offsets": [
[
133,
158
]
],
"normalized": []
},
{
"id": "bosulif_entity_M2",
"type": "AdverseReaction",
"text": [
"Myelosuppression"
... | [] | [] | [
{
"id": "bosulif_relation_RL1",
"type": "Effect",
"arg1_id": "M56",
"arg2_id": "M57",
"normalized": []
},
{
"id": "bosulif_relation_RL2",
"type": "Effect",
"arg1_id": "M59",
"arg2_id": "M60",
"normalized": []
},
{
"id": "bosulif_relation_RL3",
"type": "Effect"... |
43 | teflaro | [
{
"id": "teflaro_section_S1",
"type": "adverse reactions",
"text": [
" 6. ADVERSE REACTIONS\n\n The following serious adverse reactions are described in greater detail in the Warnings and Precautions section\n\n\n\n * Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] \n * ... | [
{
"id": "teflaro_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity Reactions"
],
"offsets": [
[
147,
173
]
],
"normalized": []
},
{
"id": "teflaro_entity_M2",
"type": "AdverseReaction",
"text": [
"Clostridium diffic... | [] | [] | [
{
"id": "teflaro_relation_RL1",
"type": "Effect",
"arg1_id": "M39",
"arg2_id": "M38",
"normalized": []
},
{
"id": "teflaro_relation_RL2",
"type": "Effect",
"arg1_id": "M40",
"arg2_id": "M38",
"normalized": []
},
{
"id": "teflaro_relation_RL3",
"type": "Hypothe... |
44 | cerdelga | [
{
"id": "cerdelga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (>=10%) are: fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIO... | [
{
"id": "cerdelga_entity_M1",
"type": "AdverseReaction",
"text": [
"fatigue"
],
"offsets": [
[
85,
92
]
],
"normalized": []
},
{
"id": "cerdelga_entity_M2",
"type": "AdverseReaction",
"text": [
"headache"
],
"offsets": [
... | [] | [] | [
{
"id": "cerdelga_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M37",
"arg2_id": "M36",
"normalized": []
},
{
"id": "cerdelga_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M42",
"arg2_id": "M41",
"normalized": []
}
] |
45 | gilotrif | [
{
"id": "gilotrif_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Diarrhea [see Warnings and Precautions (5.1)] \n * Bullous and Exfoliative Skin Disor... | [
{
"id": "gilotrif_entity_M1",
"type": "AdverseReaction",
"text": [
"Diarrhea"
],
"offsets": [
[
134,
142
]
],
"normalized": []
},
{
"id": "gilotrif_entity_M2",
"type": "AdverseReaction",
"text": [
"Bullous",
"Skin Disorders"
... | [] | [] | [
{
"id": "gilotrif_relation_RL1",
"type": "Effect",
"arg1_id": "M39",
"arg2_id": "M40",
"normalized": []
},
{
"id": "gilotrif_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M80",
"arg2_id": "M79",
"normalized": []
},
{
"id": "gilotrif_relation_RL3",
"type":... |
46 | voraxaze | [
{
"id": "voraxaze_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with VORAXAZE are paraesthesias, flushing, nausea and/or vomiting, hy... | [
{
"id": "voraxaze_entity_M1",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[
33,
40
]
],
"normalized": []
},
{
"id": "voraxaze_entity_M2",
"type": "AdverseReaction",
"text": [
"allergic reactions"
],
"offsets": [
... | [] | [] | [
{
"id": "voraxaze_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "voraxaze_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M3",
"arg2_id": "M4",
"normalized": []
},
{
"id": "voraxaze_relation_RL3",
"type": "Ef... |
47 | natazia | [
{
"id": "natazia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling:\n\n\n\n * Serious cardiovascular events and stroke [see Boxed Warning and Warnings and Precaut... | [
{
"id": "natazia_entity_M1",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[
138,
145
]
],
"normalized": []
},
{
"id": "natazia_entity_M2",
"type": "AdverseReaction",
"text": [
"cardiovascular events"
],
"offsets":... | [] | [] | [
{
"id": "natazia_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "natazia_relation_RL2",
"type": "Effect",
"arg1_id": "M95",
"arg2_id": "M94",
"normalized": []
},
{
"id": "natazia_relation_RL3",
"type": "Effect",
... |
48 | xalkori | [
{
"id": "xalkori_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Hepatotoxicity [see Warnings and Precautions (5.1) ] \n * Interstitial Lung Disease/P... | [
{
"id": "xalkori_entity_M1",
"type": "AdverseReaction",
"text": [
"Hepatotoxicity"
],
"offsets": [
[
133,
147
]
],
"normalized": []
},
{
"id": "xalkori_entity_M2",
"type": "AdverseReaction",
"text": [
"Interstitial Lung Disease"
... | [] | [] | [
{
"id": "xalkori_relation_RL1",
"type": "Effect",
"arg1_id": "M7",
"arg2_id": "M6",
"normalized": []
},
{
"id": "xalkori_relation_RL2",
"type": "Effect",
"arg1_id": "M152",
"arg2_id": "M151",
"normalized": []
},
{
"id": "xalkori_relation_RL3",
"type": "Effect"... |
49 | imbruvica | [
{
"id": "imbruvica_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n * Hemorrhage [see Warnings and Precautions (5.1) ] \n * Infections [see Warnings and Pr... | [
{
"id": "imbruvica_entity_M1",
"type": "AdverseReaction",
"text": [
"Hemorrhage"
],
"offsets": [
[
130,
140
]
],
"normalized": []
},
{
"id": "imbruvica_entity_M2",
"type": "AdverseReaction",
"text": [
"Infections"
],
"offset... | [] | [] | [
{
"id": "imbruvica_relation_RL1",
"type": "Effect",
"arg1_id": "M35",
"arg2_id": "M34",
"normalized": []
},
{
"id": "imbruvica_relation_RL2",
"type": "Effect",
"arg1_id": "M35",
"arg2_id": "M33",
"normalized": []
},
{
"id": "imbruvica_relation_RL3",
"type": "E... |
50 | pradaxa | [
{
"id": "pradaxa_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions reported with PRADAXA were related to bleeding [see Warnings and Precautions (5.2) ] .\n\n\n\n EXCERPT: Most common adverse reactions (>15%) are gastritis-... | [
{
"id": "pradaxa_entity_M1",
"type": "AdverseReaction",
"text": [
"bleeding"
],
"offsets": [
[
101,
109
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10005103"
}
]
},
{
"id": "pradaxa_entity_M2",
... | [] | [] | [
{
"id": "pradaxa_relation_RL1",
"type": "Effect",
"arg1_id": "M12",
"arg2_id": "M11",
"normalized": []
},
{
"id": "pradaxa_relation_RL2",
"type": "Effect",
"arg1_id": "M15",
"arg2_id": "M14",
"normalized": []
},
{
"id": "pradaxa_relation_RL3",
"type": "Effect"... |
51 | toviaz | [
{
"id": "toviaz_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most frequently reported adverse events (>=4%) for Toviaz were: dry mouth (placebo, 7%; Toviaz 4 mg, 19%; Toviaz 8 mg, 35%) and constipation (placebo, 2%; Toviaz 4 mg, 4%; Toviaz 8 mg, ... | [
{
"id": "toviaz_entity_M1",
"type": "AdverseReaction",
"text": [
"dry mouth"
],
"offsets": [
[
106,
115
]
],
"normalized": []
},
{
"id": "toviaz_entity_M2",
"type": "AdverseReaction",
"text": [
"constipation"
],
"offsets": [... | [] | [] | [
{
"id": "toviaz_relation_RL1",
"type": "Effect",
"arg1_id": "M36",
"arg2_id": "M38",
"normalized": []
},
{
"id": "toviaz_relation_RL2",
"type": "Effect",
"arg1_id": "M36",
"arg2_id": "M39",
"normalized": []
},
{
"id": "toviaz_relation_RL3",
"type": "Effect",
... |
52 | besivance | [
{
"id": "besivance_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with the rates in the clinical tri... | [
{
"id": "besivance_entity_M1",
"type": "AdverseReaction",
"text": [
"ocular adverse reaction"
],
"offsets": [
[
521,
544
]
],
"normalized": []
},
{
"id": "besivance_entity_M2",
"type": "AdverseReaction",
"text": [
"conjunctival redn... | [] | [] | [
{
"id": "besivance_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M10",
"arg2_id": "M9",
"normalized": []
},
{
"id": "besivance_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M11",
"arg2_id": "M9",
"normalized": []
}
] |
53 | bepreve | [
{
"id": "bepreve_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reaction occurring in approximately 25% of patients was a mild taste following instillation. Other adverse reactions which occurred in 2-5% of subjects were eye ir... | [
{
"id": "bepreve_entity_M1",
"type": "Severity",
"text": [
"mild"
],
"offsets": [
[
121,
125
]
],
"normalized": []
},
{
"id": "bepreve_entity_M2",
"type": "AdverseReaction",
"text": [
"taste following instillation"
],
"offse... | [] | [] | [
{
"id": "bepreve_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "bepreve_relation_RL2",
"type": "Effect",
"arg1_id": "M7",
"arg2_id": "M6",
"normalized": []
}
] |
54 | eliquis | [
{
"id": "eliquis_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.\n\n\n\n * ? Increased risk of thrombotic events after premature discontinua... | [
{
"id": "eliquis_entity_M1",
"type": "Factor",
"text": [
"risk"
],
"offsets": [
[
169,
173
]
],
"normalized": []
},
{
"id": "eliquis_entity_M2",
"type": "AdverseReaction",
"text": [
"thrombotic events"
],
"offsets": [
... | [] | [] | [
{
"id": "eliquis_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "eliquis_relation_RL2",
"type": "Effect",
"arg1_id": "M7",
"arg2_id": "M6",
"normalized": []
},
{
"id": "eliquis_relation_RL3",
"type": "Effec... |
55 | kalydeco | [
{
"id": "kalydeco_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reaction is discussed in greater detail in other sections of the label:\n\n\n\n * Transaminase Elevations [ see Warnings and Precautions (5.1) ] \n EXCERPT: The mo... | [
{
"id": "kalydeco_entity_M1",
"type": "AdverseReaction",
"text": [
"Transaminase Elevations"
],
"offsets": [
[
128,
151
]
],
"normalized": []
},
{
"id": "kalydeco_entity_M2",
"type": "AdverseReaction",
"text": [
"headache"
],
... | [] | [] | [
{
"id": "kalydeco_relation_RL1",
"type": "Effect",
"arg1_id": "M57",
"arg2_id": "M58",
"normalized": []
},
{
"id": "kalydeco_relation_RL2",
"type": "Effect",
"arg1_id": "M60",
"arg2_id": "M59",
"normalized": []
},
{
"id": "kalydeco_relation_RL3",
"type": "Effe... |
56 | invokana | [
{
"id": "invokana_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions (5.1) ] \n * Impairment in Renal Function [see ... | [
{
"id": "invokana_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypotension"
],
"offsets": [
[
127,
138
]
],
"normalized": []
},
{
"id": "invokana_entity_M2",
"type": "AdverseReaction",
"text": [
"Impairment in Renal Function"
... | [] | [] | [
{
"id": "invokana_relation_RL1",
"type": "Effect",
"arg1_id": "M34",
"arg2_id": "M33",
"normalized": []
},
{
"id": "invokana_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M45",
"arg2_id": "M44",
"normalized": []
},
{
"id": "invokana_relation_RL3",
"type":... |
57 | stribild | [
{
"id": "stribild_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse drug reactions are discussed in other sections of the labeling:\n\n\n\n * Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning , Warnings and Precautions (... | [
{
"id": "stribild_entity_M1",
"type": "AdverseReaction",
"text": [
"Lactic Acidosis"
],
"offsets": [
[
120,
135
]
],
"normalized": []
},
{
"id": "stribild_entity_M2",
"type": "Severity",
"text": [
"Severe"
],
"offsets": [
... | [] | [] | [
{
"id": "stribild_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "stribild_relation_RL2",
"type": "Effect",
"arg1_id": "M6",
"arg2_id": "M5",
"normalized": []
},
{
"id": "stribild_relation_RL3",
"type": "Effect",... |
58 | lumizyme | [
{
"id": "lumizyme_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * The most frequently reported adverse reactions (>= 5%) in clinical trials were hypersensitivity reactions and included: anaphylaxis, rash, pyrexia, flushing/feeling hot, urticaria, h... | [
{
"id": "lumizyme_entity_M1",
"type": "AdverseReaction",
"text": [
"hypersensitivity reactions"
],
"offsets": [
[
122,
148
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10020756"
}
]
},
{
"id": "l... | [] | [] | [
{
"id": "lumizyme_relation_RL1",
"type": "Effect",
"arg1_id": "M155",
"arg2_id": "M154",
"normalized": []
},
{
"id": "lumizyme_relation_RL2",
"type": "Effect",
"arg1_id": "M160",
"arg2_id": "M158",
"normalized": []
},
{
"id": "lumizyme_relation_RL3",
"type": "... |
59 | uloric | [
{
"id": "uloric_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Adverse reactions occurring in at least 1% of ULORIC-treated patients, and at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash. ( 6.1 )\n\n\... | [
{
"id": "uloric_entity_M1",
"type": "AdverseReaction",
"text": [
"liver function abnormalities"
],
"offsets": [
[
153,
181
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10017475"
}
]
},
{
"id": "u... | [] | [] | [
{
"id": "uloric_relation_RL1",
"type": "Effect",
"arg1_id": "M201",
"arg2_id": "M200",
"normalized": []
},
{
"id": "uloric_relation_RL2",
"type": "Effect",
"arg1_id": "M203",
"arg2_id": "M202",
"normalized": []
},
{
"id": "uloric_relation_RL3",
"type": "Effect... |
60 | jevtana | [
{
"id": "jevtana_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in another section of the label:\n\n\n\n * Bone Marrow Suppression [see Warnings and Precautions (5.1) ] . \n * Hypersensit... | [
{
"id": "jevtana_entity_M1",
"type": "AdverseReaction",
"text": [
"Bone Marrow Suppression"
],
"offsets": [
[
139,
162
]
],
"normalized": []
},
{
"id": "jevtana_entity_M2",
"type": "AdverseReaction",
"text": [
"Hypersensitivity Reac... | [] | [] | [
{
"id": "jevtana_relation_RL1",
"type": "Effect",
"arg1_id": "M40",
"arg2_id": "M39",
"normalized": []
},
{
"id": "jevtana_relation_RL2",
"type": "Effect",
"arg1_id": "M40",
"arg2_id": "M37",
"normalized": []
},
{
"id": "jevtana_relation_RL3",
"type": "Effect"... |
61 | simponi | [
{
"id": "simponi_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The most serious adverse reactions were:\n\n\n\n * Serious Infections [see Warnings and Precautions (5.1) ] \n * Malignancies [see Warnings and Precautions (5.2) ] \n EXCERPT: Most com... | [
{
"id": "simponi_entity_M1",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[
75,
82
]
],
"normalized": []
},
{
"id": "simponi_entity_M2",
"type": "AdverseReaction",
"text": [
"Infections"
],
"offsets": [
[
... | [] | [] | [
{
"id": "simponi_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "simponi_relation_RL2",
"type": "Effect",
"arg1_id": "M11",
"arg2_id": "M10",
"normalized": []
},
{
"id": "simponi_relation_RL3",
"type": "Effect",
... |
62 | intelence | [
{
"id": "intelence_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in greater detail in other sections:\n\n\n\n * Severe skin and hypersensitivity reactions [ see Warnings and Precautions (5.1) ]. \n EXCERPT: ... | [
{
"id": "intelence_entity_M1",
"type": "Severity",
"text": [
"Severe"
],
"offsets": [
[
117,
123
]
],
"normalized": []
},
{
"id": "intelence_entity_M2",
"type": "AdverseReaction",
"text": [
"skin",
"reactions"
],
"offs... | [] | [] | [
{
"id": "intelence_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "intelence_relation_RL2",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M1",
"normalized": []
},
{
"id": "intelence_relation_RL3",
"type": "Effec... |
63 | jublia | [
{
"id": "jublia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (incidence >1%) were ingrown toenails, application site dermatitis, application site vesicles, and application site pain. (6.1) \n\n\n\n To report SUSP... | [
{
"id": "jublia_entity_M1",
"type": "AdverseReaction",
"text": [
"ingrown toenails"
],
"offsets": [
[
93,
109
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10022015"
}
]
},
{
"id": "jublia_entity_... | [] | [] | [] |
64 | northera | [
{
"id": "northera_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions with NORTHERA are included in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Supine Hypertension [see Warnings and Precautions ( 5.1 )... | [
{
"id": "northera_entity_M1",
"type": "AdverseReaction",
"text": [
"Supine Hypertension"
],
"offsets": [
[
162,
181
]
],
"normalized": []
},
{
"id": "northera_entity_M2",
"type": "AdverseReaction",
"text": [
"Hyperpyrexia"
],
... | [] | [] | [
{
"id": "northera_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M5",
"arg2_id": "M4",
"normalized": []
},
{
"id": "northera_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M6",
"arg2_id": "M4",
"normalized": []
},
{
"id": "northera_relation_RL3",
"type... |
65 | kalbitor | [
{
"id": "kalbitor_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [ see Contraindications (4) and Warnings and Precautions (5.1) ].\n\n\n\n EXCERPT: ... | [
{
"id": "kalbitor_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity"
],
"offsets": [
[
28,
44
]
],
"normalized": []
},
{
"id": "kalbitor_entity_M2",
"type": "AdverseReaction",
"text": [
"anaphylaxis"
],
"off... | [] | [] | [
{
"id": "kalbitor_relation_RL1",
"type": "Effect",
"arg1_id": "M44",
"arg2_id": "M43",
"normalized": []
},
{
"id": "kalbitor_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M44",
"arg2_id": "M42",
"normalized": []
}
] |
66 | halaven | [
{
"id": "halaven_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n EXCERPT: The most common adverse reactions (incidence >=25%) were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation ( 6 )\n\n\n\n To report... | [
{
"id": "halaven_entity_M1",
"type": "AdverseReaction",
"text": [
"neutropenia"
],
"offsets": [
[
102,
113
]
],
"normalized": []
},
{
"id": "halaven_entity_M2",
"type": "AdverseReaction",
"text": [
"anemia"
],
"offsets": [
... | [] | [] | [
{
"id": "halaven_relation_RL1",
"type": "Effect",
"arg1_id": "M54",
"arg2_id": "M53",
"normalized": []
},
{
"id": "halaven_relation_RL2",
"type": "Effect",
"arg1_id": "M56",
"arg2_id": "M55",
"normalized": []
},
{
"id": "halaven_relation_RL3",
"type": "Effect"... |
67 | nesina | [
{
"id": "nesina_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Common adverse reactions (reported in >=4% of patients treated with NESINA 25 mg and more frequently than in patients who received placebo) are: nasopharyngitis, headache and upper respirat... | [
{
"id": "nesina_entity_M1",
"type": "AdverseReaction",
"text": [
"nasopharyngitis"
],
"offsets": [
[
183,
198
]
],
"normalized": []
},
{
"id": "nesina_entity_M2",
"type": "AdverseReaction",
"text": [
"headache"
],
"offsets":... | [] | [] | [
{
"id": "nesina_relation_RL1",
"type": "Effect",
"arg1_id": "M18",
"arg2_id": "M17",
"normalized": []
},
{
"id": "nesina_relation_RL2",
"type": "Effect",
"arg1_id": "M20",
"arg2_id": "M19",
"normalized": []
},
{
"id": "nesina_relation_RL3",
"type": "Negated",
... |
68 | victrelis | [
{
"id": "victrelis_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n See the peginterferon alfa and ribavirin prescribing information for description of adverse reactions associated with their use.\n\n\n\n EXCERPT: The most commonly reported adverse reactions (g... | [
{
"id": "victrelis_entity_M1",
"type": "AdverseReaction",
"text": [
"fatigue"
],
"offsets": [
[
357,
364
]
],
"normalized": []
},
{
"id": "victrelis_entity_M2",
"type": "AdverseReaction",
"text": [
"anemia"
],
"offsets": [
... | [] | [] | [
{
"id": "victrelis_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M70",
"arg2_id": "M69",
"normalized": []
},
{
"id": "victrelis_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M71",
"arg2_id": "M69",
"normalized": []
},
{
"id": "victrelis_relation_RL3",
... |
69 | zytiga | [
{
"id": "zytiga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following are discussed in more detail in other sections of the labeling:\n\n\n\n * Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [seeWarnings and Precautions (5.... | [
{
"id": "zytiga_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypertension"
],
"offsets": [
[
112,
124
]
],
"normalized": []
},
{
"id": "zytiga_entity_M2",
"type": "AdverseReaction",
"text": [
"Hypokalemia"
],
"offsets":... | [] | [] | [
{
"id": "zytiga_relation_RL1",
"type": "Effect",
"arg1_id": "M72",
"arg2_id": "M69",
"normalized": []
},
{
"id": "zytiga_relation_RL2",
"type": "Effect",
"arg1_id": "M72",
"arg2_id": "M70",
"normalized": []
},
{
"id": "zytiga_relation_RL3",
"type": "Effect",
... |
70 | inlyta | [
{
"id": "inlyta_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n 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 a... | [
{
"id": "inlyta_entity_M1",
"type": "Factor",
"text": [
"risks"
],
"offsets": [
[
656,
661
]
],
"normalized": []
},
{
"id": "inlyta_entity_M2",
"type": "AdverseReaction",
"text": [
"hypertension"
],
"offsets": [
[
... | [] | [] | [
{
"id": "inlyta_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "inlyta_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M3",
"arg2_id": "M1",
"normalized": []
},
{
"id": "inlyta_relation_RL3",
"type": "Hy... |
71 | vimizim | [
{
"id": "vimizim_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n 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 ... | [
{
"id": "vimizim_entity_M1",
"type": "AdverseReaction",
"text": [
"Anaphylaxis"
],
"offsets": [
[
392,
403
]
],
"normalized": []
},
{
"id": "vimizim_entity_M2",
"type": "AdverseReaction",
"text": [
"hypersensitivity reactions"
]... | [] | [] | [
{
"id": "vimizim_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M18",
"arg2_id": "M17",
"normalized": []
},
{
"id": "vimizim_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M20",
"arg2_id": "M19",
"normalized": []
},
{
"id": "vimizim_relation_RL3",
"typ... |
72 | afinitor | [
{
"id": "afinitor_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in another section of the label [see Warnings and Precautions (5)] :\n\n\n\n * Non-infectious pneumonitis [see Warnings... | [
{
"id": "afinitor_entity_M1",
"type": "AdverseReaction",
"text": [
"Non-infectious pneumonitis"
],
"offsets": [
[
181,
207
]
],
"normalized": []
},
{
"id": "afinitor_entity_M2",
"type": "AdverseReaction",
"text": [
"Infections"
... | [] | [] | [
{
"id": "afinitor_relation_RL1",
"type": "Effect",
"arg1_id": "M31",
"arg2_id": "M30",
"normalized": []
},
{
"id": "afinitor_relation_RL2",
"type": "Effect",
"arg1_id": "M31",
"arg2_id": "M29",
"normalized": []
},
{
"id": "afinitor_relation_RL3",
"type": "Effe... |
73 | gadavist | [
{
"id": "gadavist_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n * The following serious adverse reactions are discussed elsewhere in labeling: \n * Nephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions ( 5.1 )]. \n Hyp... | [
{
"id": "gadavist_entity_M1",
"type": "AdverseReaction",
"text": [
"Nephrogenic Systemic Fibrosis"
],
"offsets": [
[
118,
147
]
],
"normalized": []
},
{
"id": "gadavist_entity_M2",
"type": "AdverseReaction",
"text": [
"NSF"
],
... | [] | [] | [
{
"id": "gadavist_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M66",
"arg2_id": "M65",
"normalized": []
},
{
"id": "gadavist_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M66",
"arg2_id": "M64",
"normalized": []
},
{
"id": "gadavist_relation_RL3",
"... |
74 | firazyr | [
{
"id": "firazyr_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most commonly reported adverse reactions were injection site reactions, which occurred in almost all patients (97%) in clinical trials. Other common adverse reactions occurring in grea... | [
{
"id": "firazyr_entity_M1",
"type": "AdverseReaction",
"text": [
"injection site reactions"
],
"offsets": [
[
88,
112
]
],
"normalized": []
},
{
"id": "firazyr_entity_M2",
"type": "AdverseReaction",
"text": [
"pyrexia"
],
"... | [] | [] | [
{
"id": "firazyr_relation_RL1",
"type": "Negated",
"arg1_id": "M14",
"arg2_id": "M13",
"normalized": []
},
{
"id": "firazyr_relation_RL2",
"type": "Negated",
"arg1_id": "M15",
"arg2_id": "M13",
"normalized": []
}
] |
75 | carbaglu | [
{
"id": "carbaglu_section_S1",
"type": "adverse reactions",
"text": [
" EXCERPT: The most common adverse reactions in >=13% of patients are: Infections, vomiting, abdominal pain, pyrexia, tonsilitis, anemia, ear infection, diarrhea, nasopharyngitis, and headache. ( 6.1 )\n\n\n\n To report... | [
{
"id": "carbaglu_entity_M1",
"type": "AdverseReaction",
"text": [
"Infections"
],
"offsets": [
[
75,
85
]
],
"normalized": []
},
{
"id": "carbaglu_entity_M2",
"type": "AdverseReaction",
"text": [
"vomiting"
],
"offsets": [
... | [] | [] | [] |
76 | tafinlar | [
{
"id": "tafinlar_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in another section of the label:\n\n\n\n * New Primary Malignancies [see Warnings and Precautions (5.1)] \n * Tumor Promotion i... | [
{
"id": "tafinlar_entity_M1",
"type": "AdverseReaction",
"text": [
"Primary Malignancies"
],
"offsets": [
[
137,
157
]
],
"normalized": []
},
{
"id": "tafinlar_entity_M2",
"type": "AdverseReaction",
"text": [
"Tumor Promotion in BRA... | [] | [] | [
{
"id": "tafinlar_relation_RL1",
"type": "Effect",
"arg1_id": "M8",
"arg2_id": "M7",
"normalized": []
},
{
"id": "tafinlar_relation_RL2",
"type": "Effect",
"arg1_id": "M10",
"arg2_id": "M9",
"normalized": []
},
{
"id": "tafinlar_relation_RL3",
"type": "Effect"... |
77 | xeomin | [
{
"id": "xeomin_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions to XEOMIN are discussed in greater detail in other sections of the labeling:\n\n\n\n * Hypersensitivity [ see Contraindications (4) and Warnings and Precautions (5.... | [
{
"id": "xeomin_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity"
],
"offsets": [
[
143,
159
]
],
"normalized": []
},
{
"id": "xeomin_entity_M2",
"type": "AdverseReaction",
"text": [
"Dysphagia"
],
"offsets... | [] | [] | [
{
"id": "xeomin_relation_RL1",
"type": "Effect",
"arg1_id": "M42",
"arg2_id": "M41",
"normalized": []
},
{
"id": "xeomin_relation_RL2",
"type": "Negated",
"arg1_id": "M42",
"arg2_id": "M40",
"normalized": []
},
{
"id": "xeomin_relation_RL3",
"type": "Hypotheti... |
78 | erwinaze | [
{
"id": "erwinaze_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed in greater detail in other sections of the label:\n\n\n\n * Hypersensitivity reactions [ see Warnings and Precautions (5.1) ] \n * Pancrea... | [
{
"id": "erwinaze_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity reactions"
],
"offsets": [
[
140,
166
]
],
"normalized": []
},
{
"id": "erwinaze_entity_M2",
"type": "AdverseReaction",
"text": [
"Pancreatitis"
... | [] | [] | [
{
"id": "erwinaze_relation_RL1",
"type": "Negated",
"arg1_id": "M49",
"arg2_id": "M48",
"normalized": []
},
{
"id": "erwinaze_relation_RL2",
"type": "Negated",
"arg1_id": "M50",
"arg2_id": "M48",
"normalized": []
},
{
"id": "erwinaze_relation_RL3",
"type": "Ne... |
79 | aptiom | [
{
"id": "aptiom_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:\n\n\n\n * Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.1 )] ... | [
{
"id": "aptiom_entity_M1",
"type": "AdverseReaction",
"text": [
"Suicidal Behavior"
],
"offsets": [
[
151,
168
]
],
"normalized": []
},
{
"id": "aptiom_entity_M2",
"type": "AdverseReaction",
"text": [
"Suicidal",
"Ideation"
... | [] | [] | [
{
"id": "aptiom_relation_RL1",
"type": "Effect",
"arg1_id": "M4",
"arg2_id": "M3",
"normalized": []
},
{
"id": "aptiom_relation_RL2",
"type": "Effect",
"arg1_id": "M89",
"arg2_id": "M88",
"normalized": []
},
{
"id": "aptiom_relation_RL3",
"type": "Hypothetical... |
80 | eylea | [
{
"id": "eylea_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in the Warnings and Precautions (5) section of the labeling:\n\n\n\n * Endophthalmitis and retinal detachments \n * Increased intraoc... | [
{
"id": "eylea_entity_M1",
"type": "AdverseReaction",
"text": [
"Endophthalmitis"
],
"offsets": [
[
161,
176
]
],
"normalized": []
},
{
"id": "eylea_entity_M2",
"type": "AdverseReaction",
"text": [
"retinal detachments"
],
"... | [] | [] | [
{
"id": "eylea_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M78",
"arg2_id": "M80",
"normalized": []
},
{
"id": "eylea_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M79",
"arg2_id": "M80",
"normalized": []
},
{
"id": "eylea_relation_RL3",
"type": "H... |
81 | cleviprex | [
{
"id": "cleviprex_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following risk is discussed elsewhere in the labeling:\n\n\n\n * Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)] \n EXCERPT: Most common adverse reactions (... | [
{
"id": "cleviprex_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypotension"
],
"offsets": [
[
93,
104
]
],
"normalized": []
},
{
"id": "cleviprex_entity_M2",
"type": "AdverseReaction",
"text": [
"Reflex Tachycardia"
],
... | [] | [] | [
{
"id": "cleviprex_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M23",
"arg2_id": "M22",
"normalized": []
},
{
"id": "cleviprex_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M25",
"arg2_id": "M27",
"normalized": []
},
{
"id": "cleviprex_relation_RL3",
... |
82 | farxiga | [
{
"id": "farxiga_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described below and elsewhere in the labeling:\n\n\n\n * Hypotension [see Warnings and Precautions (5.1) ] \n * Impairment in Renal Function [se... | [
{
"id": "farxiga_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypotension"
],
"offsets": [
[
129,
140
]
],
"normalized": []
},
{
"id": "farxiga_entity_M2",
"type": "AdverseReaction",
"text": [
"Impairment in Renal Function"
... | [] | [] | [
{
"id": "farxiga_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M57",
"arg2_id": "M56",
"normalized": []
},
{
"id": "farxiga_relation_RL2",
"type": "Effect",
"arg1_id": "M83",
"arg2_id": "M82",
"normalized": []
},
{
"id": "farxiga_relation_RL3",
"type": "E... |
83 | trulicity | [
{
"id": "trulicity_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious reactions are described below or elsewhere in the prescribing information:\n\n\n\n * Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] \n * Pancreatiti... | [
{
"id": "trulicity_entity_M1",
"type": "Factor",
"text": [
"Risk"
],
"offsets": [
[
131,
135
]
],
"normalized": []
},
{
"id": "trulicity_entity_M2",
"type": "AdverseReaction",
"text": [
"Thyroid C-cell Tumors"
],
"offsets": ... | [] | [] | [
{
"id": "trulicity_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "trulicity_relation_RL2",
"type": "Effect",
"arg1_id": "M8",
"arg2_id": "M7",
"normalized": []
},
{
"id": "trulicity_relation_RL3",
"type": ... |
84 | cimzia | [
{
"id": "cimzia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common adverse reactions (incidence >=7% and higher than placebo): upper respiratory tract infection, rash, and urinary tract infection ( 6.1 ) To report SUSPECTED ADVERSE REACT... | [
{
"id": "cimzia_entity_M1",
"type": "AdverseReaction",
"text": [
"upper respiratory tract infection"
],
"offsets": [
[
114,
147
]
],
"normalized": []
},
{
"id": "cimzia_entity_M2",
"type": "AdverseReaction",
"text": [
"rash"
],
... | [] | [] | [
{
"id": "cimzia_relation_RL1",
"type": "Effect",
"arg1_id": "M5",
"arg2_id": "M4",
"normalized": []
},
{
"id": "cimzia_relation_RL2",
"type": "Effect",
"arg1_id": "M78",
"arg2_id": "M77",
"normalized": []
},
{
"id": "cimzia_relation_RL3",
"type": "Effect",
... |
85 | tudorza | [
{
"id": "tudorza_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are described in greater detail in other sections:\n\n\n\n * Paradoxical bronchospasm [see Warnings and Precautions (5.2)] \n * Worsening of narrow-angle glauco... | [
{
"id": "tudorza_entity_M1",
"type": "AdverseReaction",
"text": [
"Paradoxical bronchospasm"
],
"offsets": [
[
119,
143
]
],
"normalized": []
},
{
"id": "tudorza_entity_M2",
"type": "AdverseReaction",
"text": [
"Worsening of narrow-... | [] | [] | [
{
"id": "tudorza_relation_RL1",
"type": "Effect",
"arg1_id": "M20",
"arg2_id": "M19",
"normalized": []
},
{
"id": "tudorza_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M35",
"arg2_id": "M36",
"normalized": []
},
{
"id": "tudorza_relation_RL3",
"type": "H... |
86 | saphris | [
{
"id": "saphris_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in more detail in other sections of the labeling:\n\n\n\n * Use in Elderly Patients with Dementia-Related Psychosis [seeBoxed Warningand Warnings and Pr... | [
{
"id": "saphris_entity_M1",
"type": "AdverseReaction",
"text": [
"Neuroleptic Malignant Syndrome"
],
"offsets": [
[
251,
281
]
],
"normalized": []
},
{
"id": "saphris_entity_M2",
"type": "AdverseReaction",
"text": [
"Tardive Dyskin... | [] | [] | [
{
"id": "saphris_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M21",
"arg2_id": "M20",
"normalized": []
},
{
"id": "saphris_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M22",
"arg2_id": "M20",
"normalized": []
},
{
"id": "saphris_relation_RL3",
"typ... |
87 | neuraceq | [
{
"id": "neuraceq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n \n\n\n\n EXCERPT: The most commonly reported adverse reactions were: injection site reaction consisting of erythema (1.7 %), irritation (1.2 %), and pain (3.9 %).\n\n\n\n To report SUSPECTED A... | [
{
"id": "neuraceq_entity_M1",
"type": "AdverseReaction",
"text": [
"injection site reaction"
],
"offsets": [
[
96,
119
]
],
"normalized": []
},
{
"id": "neuraceq_entity_M2",
"type": "AdverseReaction",
"text": [
"injection site",
... | [] | [] | [
{
"id": "neuraceq_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M17",
"arg2_id": "M16",
"normalized": []
}
] |
88 | prolia | [
{
"id": "prolia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious adverse reactions are discussed below and also elsewhere in the labeling:\n\n\n\n * Hypocalcemia [see Warnings and Precautions ( 5.3 )] \n * Serious Infections [see Warnings... | [
{
"id": "prolia_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypocalcemia"
],
"offsets": [
[
130,
142
]
],
"normalized": []
},
{
"id": "prolia_entity_M2",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[
... | [] | [] | [
{
"id": "prolia_relation_RL1",
"type": "Effect",
"arg1_id": "M3",
"arg2_id": "M2",
"normalized": []
},
{
"id": "prolia_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M65",
"arg2_id": "M64",
"normalized": []
},
{
"id": "prolia_relation_RL3",
"type": "Effect... |
89 | kyprolis | [
{
"id": "kyprolis_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following adverse reactions are discussed in greater detail in other sections of the labeling:\n\n\n\n * Cardiac Toxicities [ see Warnings and Precautions ( 5.1 ) ] \n * Acute Renal Fail... | [
{
"id": "kyprolis_entity_M1",
"type": "AdverseReaction",
"text": [
"Cardiac Toxicities"
],
"offsets": [
[
135,
153
]
],
"normalized": []
},
{
"id": "kyprolis_entity_M2",
"type": "AdverseReaction",
"text": [
"Acute Renal Failure"
... | [] | [] | [
{
"id": "kyprolis_relation_RL1",
"type": "Effect",
"arg1_id": "M146",
"arg2_id": "M145",
"normalized": []
},
{
"id": "kyprolis_relation_RL2",
"type": "Effect",
"arg1_id": "M147",
"arg2_id": "M145",
"normalized": []
},
{
"id": "kyprolis_relation_RL3",
"type": "... |
90 | zerbaxa | [
{
"id": "zerbaxa_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following serious reactions are described in greater detail in the Warnings and Precautions section:\n\n\n\n * Hypersensitivity reactions [see Warnings and Precautions (5.2) ] \n * Clostrid... | [
{
"id": "zerbaxa_entity_M1",
"type": "AdverseReaction",
"text": [
"Hypersensitivity reactions"
],
"offsets": [
[
139,
165
]
],
"normalized": []
},
{
"id": "zerbaxa_entity_M2",
"type": "AdverseReaction",
"text": [
"Clostridium diffic... | [] | [] | [
{
"id": "zerbaxa_relation_RL1",
"type": "Effect",
"arg1_id": "M62",
"arg2_id": "M61",
"normalized": []
},
{
"id": "zerbaxa_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M62",
"arg2_id": "M64",
"normalized": []
},
{
"id": "zerbaxa_relation_RL3",
"type": "E... |
91 | dotarem | [
{
"id": "dotarem_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n GBCAs have been associated with a risk for NSF [see Warnings and Precautions ( 5.1 )] . NSF has not been reported in patients with a clear history of exposure to DOTAREM alone.\n\n\n\n Hypersensi... | [
{
"id": "dotarem_entity_M1",
"type": "DrugClass",
"text": [
"GBCAs"
],
"offsets": [
[
27,
32
]
],
"normalized": []
},
{
"id": "dotarem_entity_M2",
"type": "AdverseReaction",
"text": [
"NSF"
],
"offsets": [
[
70... | [] | [] | [
{
"id": "dotarem_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "dotarem_relation_RL2",
"type": "Negated",
"arg1_id": "M3",
"arg2_id": "M4",
"normalized": []
},
{
"id": "dotarem_relation_RL3",
"type": "Hypo... |
92 | breo | [
{
"id": "breo_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhal... | [
{
"id": "breo_entity_M1",
"type": "Factor",
"text": [
"risk"
],
"offsets": [
[
115,
119
]
],
"normalized": []
},
{
"id": "breo_entity_M2",
"type": "AdverseReaction",
"text": [
"death"
],
"offsets": [
[
138,
... | [] | [] | [
{
"id": "breo_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "breo_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M3",
"arg2_id": "M4",
"normalized": []
},
{
"id": "breo_relation_RL3",
"type": "Hypothet... |
93 | adreview | [
{
"id": "adreview_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection si... | [
{
"id": "adreview_entity_M1",
"type": "Severity",
"text": [
"Serious"
],
"offsets": [
[
38,
45
]
],
"normalized": []
},
{
"id": "adreview_entity_M2",
"type": "AdverseReaction",
"text": [
"hypersensitivity reactions"
],
"offs... | [] | [] | [
{
"id": "adreview_relation_RL1",
"type": "Effect",
"arg1_id": "M2",
"arg2_id": "M1",
"normalized": []
},
{
"id": "adreview_relation_RL2",
"type": "Effect",
"arg1_id": "M11",
"arg2_id": "M9",
"normalized": []
},
{
"id": "adreview_relation_RL3",
"type": "Effect"... |
94 | ampyra | [
{
"id": "ampyra_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies o... | [
{
"id": "ampyra_entity_M1",
"type": "AdverseReaction",
"text": [
"Seizures"
],
"offsets": [
[
413,
421
]
],
"normalized": []
},
{
"id": "ampyra_entity_M2",
"type": "AdverseReaction",
"text": [
"Anaphylaxis"
],
"offsets": [
... | [] | [] | [
{
"id": "ampyra_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M38",
"arg2_id": "M37",
"normalized": []
},
{
"id": "ampyra_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M40",
"arg2_id": "M39",
"normalized": []
},
{
"id": "ampyra_relation_RL3",
"type":... |
95 | tecfidera | [
{
"id": "tecfidera_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n The following important adverse reactions are described elsewhere in labeling:\n\n\n\n * Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.1 )]. \n * Progressive multifocal leukoenc... | [
{
"id": "tecfidera_entity_M1",
"type": "AdverseReaction",
"text": [
"Anaphylaxis"
],
"offsets": [
[
113,
124
]
],
"normalized": []
},
{
"id": "tecfidera_entity_M2",
"type": "AdverseReaction",
"text": [
"Angioedema"
],
"offse... | [] | [] | [
{
"id": "tecfidera_relation_RL1",
"type": "Effect",
"arg1_id": "M35",
"arg2_id": "M34",
"normalized": []
},
{
"id": "tecfidera_relation_RL2",
"type": "Negated",
"arg1_id": "M40",
"arg2_id": "M39",
"normalized": []
},
{
"id": "tecfidera_relation_RL3",
"type": "... |
96 | amyvid | [
{
"id": "amyvid_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: The most common reported adverse reaction was headache, occurring in 2% of patients, followed by musculoskeletal pain, blood pressure increased, fatigue, nausea, and injection site reaction... | [
{
"id": "amyvid_entity_M1",
"type": "AdverseReaction",
"text": [
"headache"
],
"offsets": [
[
84,
92
]
],
"normalized": []
},
{
"id": "amyvid_entity_M2",
"type": "AdverseReaction",
"text": [
"musculoskeletal pain"
],
"offset... | [] | [] | [
{
"id": "amyvid_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M37",
"arg2_id": "M36",
"normalized": []
}
] |
97 | fulyzaq | [
{
"id": "fulyzaq_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n 6.1 Clinical Trials Experience \n\n\n\n Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot ... | [
{
"id": "fulyzaq_entity_M1",
"type": "AdverseReaction",
"text": [
"Upper respiratory tract infection"
],
"offsets": [
[
1301,
1334
]
],
"normalized": []
},
{
"id": "fulyzaq_entity_M2",
"type": "AdverseReaction",
"text": [
"Bronchiti... | [] | [] | [] |
98 | otezla | [
{
"id": "otezla_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS\n\n EXCERPT: * Psoriatic Arthritis : The most common adverse reactions (>=5%) are diarrhea, nausea, and headache (6.1) \n * Psoriasis : The most common adverse reactions (>=5%) are diarrhea, nause... | [
{
"id": "otezla_entity_M1",
"type": "AdverseReaction",
"text": [
"diarrhea"
],
"offsets": [
[
111,
119
]
],
"normalized": [
{
"db_name": "MedDRA v18.1",
"db_id": "llt_10012727"
}
]
},
{
"id": "otezla_entity_M2",
... | [] | [] | [
{
"id": "otezla_relation_RL1",
"type": "Effect",
"arg1_id": "M17",
"arg2_id": "M16",
"normalized": []
},
{
"id": "otezla_relation_RL2",
"type": "Effect",
"arg1_id": "M18",
"arg2_id": "M16",
"normalized": []
},
{
"id": "otezla_relation_RL3",
"type": "Effect",
... |
99 | ulesfia | [
{
"id": "ulesfia_section_S1",
"type": "adverse reactions",
"text": [
" 6 ADVERSE REACTIONS \n\n EXCERPT: Most common adverse reactions (> 1% and more common than with placebo): ocular irritation, application site irritation, and application site anesthesia and hypoesthesia. ( ... | [
{
"id": "ulesfia_entity_M1",
"type": "AdverseReaction",
"text": [
"ocular irritation"
],
"offsets": [
[
126,
143
]
],
"normalized": []
},
{
"id": "ulesfia_entity_M2",
"type": "AdverseReaction",
"text": [
"application site irritation... | [] | [] | [
{
"id": "ulesfia_relation_RL1",
"type": "Hypothetical",
"arg1_id": "M29",
"arg2_id": "M28",
"normalized": []
},
{
"id": "ulesfia_relation_RL2",
"type": "Hypothetical",
"arg1_id": "M31",
"arg2_id": "M32",
"normalized": []
},
{
"id": "ulesfia_relation_RL3",
"typ... |
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