Recorlev

WARNING: HEPATOTOXICITY AND QT PROLONGATION Hepatotoxicity • Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with use of oral ketoconazole. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV [see Warnings and Precautions ( 5.1 )]. • RECORLEV is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. • Evaluate liver enzymes prior to and during treatment. Interrupt RECORLEV treatment immediately if signs of hepatotoxicity occur [see Dosage and Administration ( 2.1 , 2.3 , 2.4 ), Warnings and Precautions ( 5.1 )]. QT Prolongation • RECORLEV is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias such as torsades de pointes [see Warnings and Precautions ( 5.2 )]. • Coadministration of RECORLEV with other drugs that prolong the QT interval associated with ventricular arrhythmias, including torsades de pointes, and use in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) are contraindicated [see Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )]. • Perform an ECG and correct hypokalemia and hypomagnesemia prior to and during treatment. Temporarily discontinue RECORLEV if QTcF interval exceeds 500 msec [Dosage and Administration ( 2.1 , 2.3 , 2.4 )]. WARNING: HEPATOTOXICITY AND QT PROLONGATION See full prescribing information for complete boxed warning. Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. RECORLEV is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment ( 5.1 ) RECORLEV is associated with dose-related QT interval prolongation. QT interval prolongation may result in life-threatening ventricular dysrhythmias such as torsades de pointes. Perform ECG prior to and during treatment ( 5.2 )

5 WARNINGS AND PRECAUTIONS Hypocortisolism : Hypocortisolism has been reported with RECORLEV. Monitor patients for hypocortisolism. Dosage reduction or interruption may be necessary ( 5.3 ) Hypersensitivity Reactions: Hypersensitivity to RECORLEV has been reported. Anaphylaxis has been reported with oral ketoconazole ( 5.4 ) Risks Related to Decreased Testosterone : RECORLEV may lower serum testosterone in men and women. Inform patients to report associated symptoms ( 5.5 ) 5.1 Hepatotoxicity Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV. RECORLEV is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease [see Contraindications ( 4 )] . Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV [see Drug Interactions ( 7.3 )] . Prompt recognition of liver injury is essential. At baseline, obtain liver tests [see Dosage and Administration ( 2.1 )] . During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration [see Dosage and Administration ( 2.3 )] . Permanently discontinue RECORLEV treatment immediately if AST or ALT exceeds or is equal to 5 times the upper limit of normal, or AST or ALT exceeds or is equal to 3 times the upper limit of normal and total bilirubin concentration increases to more than 2 times the upper limit of normal. Repeat liver tests within approximately 3 days following the initial abnormal liver test, until the levels are stable. Monitor at regular intervals thereafter, no less than every 7 to 10 days, until resolution of the abnormality (or return to baseline levels) or until an alternative cause has been identified [see Dosage and Administration ( 2.4 )]. For AST or ALT elevations less than 3 times the upper limit of normal, or AST or ALT elevations equal to or greater than 3 to less than 5 times the upper limit of normal and total bilirubin concentration less than 2 times the upper limit of normal, monitor liver tests and manage hepatotoxicity with RECORLEV dosage interruption or modifications [see Dosage and Administration ( 2.4 )] . If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV. 5.2 QT Prolongation RECORLEV is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias such as torsades de pointes. During Studies 1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities. RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes [see Drug Interactions ( 7.1 , 7.2 )] . RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) [see Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )]. Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment [see Dosage and Administration ( 2.1 , 2.3 )] . Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV [see Dosage and Administration ( 2.4 )] . 5.3 Hypocortisolism RECORLEV lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Adrenal insufficiency was observed in 7% of patients during the clinical program of RECORLEV [see Adverse Reactions ( 6.1 )] . Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Hypocortisolism may occur at any time during RECORLEV treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms periodically during RECORLEV treatment [see Dosage and Administration ( 2.3 )] . Decrease the dosage or temporarily discontinue RECORLEV if urine free cortisol or morning blood cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, or if signs and/or symptoms consistent with hypocortisolism are reported [see Dosage and Administration ( 2.4 )] . Stop RECORLEV and administer exogenous glucocorticoid replacement therapy if morning serum or plasma cortisol levels are below target range and signs and/or symptoms of adrenal insufficiency, or hypocortisolism, are present. After RECORLEV discontinuation, cortisol suppression may persist beyond the 4- to 6- hour half-life of RECORLEV. If treatment is interrupted due to hypocortisolism, re-initiate RECORLEV at a lower dosage when cortisol levels are within target ranges and patient’s signs and/or symptoms have resolved [see Dosage and Administration ( 2.4 )] . The dosage may be titrated to the previous dose associated with hypocortisolism if the reduced dosage has been well tolerated and the reduced dosage does not achieve an adequate clinical response. Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur. 5.4 Hypersensitivity Reactions Hypersensitivity reactions have been reported in 1% of patients treated with RECORLEV in the clinical trials [see Adverse Reactions ( 6.1 )] . Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole [see Adverse Reactions ( 6.2 )]. RECORLEV is contraindicated in patients with a known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV. 5.5 Risks Related to Decreased Testosterone RECORLEV may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes. Inform patients of the symptoms associated with low testosterone levels and advise patients to contact a healthcare provider if they occur.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] QT Prolongation [see Warnings and Precautions ( 5.2 )] Hypocortisolism [see Warnings and Precautions ( 5.3 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] Risks related to Decreased Testosterone [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence > 20%) are nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of RECORLEV was evaluated in a multicenter, randomized-withdrawal study (Study 1) and in a multicenter, single-arm, open-label study (Study 2). During the two studies, 166 patients were exposed to RECORLEV, of which 104 patients were exposed for more than 6 months and 51 patients were exposed for at least 1 year. In both studies, most patients took RECORLEV twice daily in total daily dosages ranging from 300 mg to 1200 mg [see Clinical Studies ( 14 )] . Adverse reactions, excluding hepatic injury, reported in ≥10% of patients treated with RECORLEV in Study 1 are presented in Table 2listed in order of overall decreasing frequency of events. Table 2: Adverse Reactions, Excluding Hepatic Injury, Occurring in ≥10% of Cushing’s Syndrome Patients Treated with RECORLEV in Study 1 N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event. a Hemorrhage/contusion includes blood urine present, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemorrhoidal hemorrhage, melena, and scleral hemorrhage. b Arrhythmia includes electrocardiogram QT prolonged, electrocardiogram T wave abnormal, palpitations, sinus tachycardia, tachycardia paroxysmal, and ventricular extrasystoles. c Abdominal pain/dyspepsia includes abdominal pain, abdominal distension, dyspepsia, gastric disorder, and related terms Adverse Reaction Types N= 84 n (%) Nausea/Vomiting 25 (30%) Hypokalemia 24 (29%) Systemic hypertension 20 (24%) Hemorrhage/Contusion a 19 (23%) Headache 18 (21%) Abnormal uterine bleeding 17 (20%) Arrhythmia b 16 (19%) Fatigue 15 (18%) Upper respiratory infection 15 (18%) Abdominal pain/Dyspepsia c 13 (15%) Dizziness 13 (15%) Diarrhea 13 (15%) Decreased appetite 11 (13%) Dry mouth 9 (11%) Dry skin 9 (11%) Adrenal insufficiency 8 (10%) Other notable adverse reactions which occurred with a frequency less than 10% during Study 1 were: alopecia (6%), gastrointestinal infection (6%), urinary tract infection (6%), hypogonadism (2%), and hypersensitivity (1%). Adverse reactions, excluding hepatic injury, reported in ≥10% of patients treated with RECORLEV in Study 2 are presented in Table 3listed in order of overall decreasing frequency of events. Table 3: Adverse Reactions, Excluding Hepatic Injury, Occurring in ≥10% of Cushing’s Syndrome Patients Treated with RECORLEV in Study 2 N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event. a Erythema includes flushing. b Hemorrhage/Contusion includes blood urine present, conjunctival hemorrhage, ecchymosis, epistaxis, hematoma, hyphemia, and red blood cells urine. c Abdominal pain/dyspepsia includes abdominal discomfort, abdominal distension, dyspepsia, gastritis, and other related terms. d Arrhythmia includes bradycardia, carotid pulse increased, defect conduction intraventricular, electrocardiogram QT prolonged, electrocardiogram T wave abnormal, heart rate increased, palpitations and sinus bradycardia. Adverse Reaction Type N = 94 n (%) Erythema a 40 (43%) Hemorrhage/Contusion b 38 (40%) Fatigue 37 (39%) Headache 36 (38%) Nausea/Vomiting 35 (37%) Abdominal pain/dyspepsia c 31 (33%) Arthritis 26 (28%) Upper respiratory infection 26 (28%) Myalgia 24 (26%) Abnormal uterine bleeding 23 (24%) Arrhythmia d 23 (24%) Back pain 21 (22%) Insomnia/Sleep disturbances 21 (22%) Peripheral edema 19 (20%) Systemic hypertension 19 (20%) Diarrhea 18 (19%) Pre-Syncope/Syncope 17 (18%) Rash 16 (17%) Urinary tract infection 15 (16%) Hypokalemia 14 (15%) Pruritus 14 (15%) Disturbance in attention 13 (14%) Irritability 13 (14%) Depression 11 (12%) Dry skin 11 (12%) Alopecia 10 (11%) Other notable adverse reactions which occurred with a frequency less than 10% during Study 2 were: gastrointestinal infections (5%), decreased libido (5%), hypogonadism (4%), adrenal insufficiency (3%), and gynecomastia (3%). Description of Selected Adverse Reactions Hepatic Injury and Elevated Liver Function Tests Liver-related adverse reactions reported in patients treated with RECORLEV in Studies 1 and 2 are presented in Table 4. Table 5summarizes patients who had at least one ALT or AST measurement greater than the upper limit of reference range (ULN) in post baseline visits in Studies 1 and 2 combined who had tests in the normal range at baseline. There were 11 out of 166 patients who had an AST or ALT above the ULN to ˂3 x ULN at baseline. Of these patients, 3 had increases above 3 x ULN, and none had increases above 5 x ULN. Liver test abnormalities improved with cessation of medication. Table 4: Hepatic Injury and Other Liver-Related Adverse Reactions Occurring in Cushing’s Syndrome Patients Treated with RECORLEV in Studies 1 and 2 N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event. a Liver enzyme elevation refers to elevation in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or gamma-glutamyl transferase. N = 166 n (%) At least one liver related adverse reaction 45 (27%) Liver enzyme elevation a 33 (20%) Drug-induced liver injury 3 (2%) Hepatic pain 7 (4%) Hepatic steatosis 1 (1%) Liver disorders 4 (2%) Table 5: Elevations in AST or ALT post baseline in Cushing’s Syndrome Patients Treated with RECORLEV who had AST/ALT ≤ ULN at baseline in Studies 1 and 2 N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event. a Not all elevations in liver enzymes were reported as adverse reactions during the studies. N = 155 n (%) a Time to Event in Days Median (Range) AST or ALT > ULN 70 (45%) 73 (1-334) AST or ALT >3 x ULN 17 (11%) 83 (26-232) AST or ALT >5 x ULN 7 (5%) 104 (29-232) AST or ALT >10 x ULN 4 (3%) 166 (36-252) QTc Interval Prolongation In Study 1 and 2, there were 4 (2.4%) patients who experienced QTcF>500 msec, and 23 (14.7%) patients who experienced change-from-baseline QTcF >60 msec, respectively [see Warnings and Precautions ( 5.2 )] . Adverse reactions reported around the same time that may have been associated with QT prolongation included fatigue, hypertension, nausea/vomiting, and ventricular extrasystoles (see Tables 2and 3). Hypocortisolism Hypocortisolism was reported in 11 (7%) of 166 patients across Studies 1 and 2, with events starting on median study day 96 (range 26-166). The majority of cases were managed by reducing the dosage or temporarily interrupting treatment with RECORLEV. 6.2 Postmarketing Experience The following adverse reactions have been identified from published reports or postmarketing experience with ketoconazole. 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 ketoconazole exposure. Blood and Lymphatic System Disorders : thrombocytopenia Endocrine Disorders: adrenocortical insufficiency Hepatobiliary Disorders: serious hepatotoxicity including hepatitis cholestatic, biopsy-confirmed hepatic necrosis, cirrhosis, hepatic failure including cases resulting in transplantation or death Immune System Disorders: allergic conditions including anaphylactic shock, anaphylactic reaction, angioneurotic edema Nervous System Disorders: reversible intracranial pressure increased (e.g., papilledema, fontanelle bulging in infants) Reproductive System and Breast Disorders: erectile dysfunction; with dosages higher than 200 or 400mg daily, azoospermia. Skin and Subcutaneous Tissue Disorders: acute generalized exanthematous pustulosis, photosensitivity

<table><caption>Table 2: Adverse Reactions, Excluding Hepatic Injury, Occurring in &#x2265;10% of Cushing&#x2019;s Syndrome Patients Treated with RECORLEV in Study 1</caption><col width="25%"/><col width="25%"/><tfoot><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule">N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event. <paragraph>^aHemorrhage/contusion includes blood urine present, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemorrhoidal hemorrhage, melena, and scleral hemorrhage. </paragraph><paragraph>^bArrhythmia includes electrocardiogram QT prolonged, electrocardiogram T wave abnormal, palpitations, sinus tachycardia, tachycardia paroxysmal, and ventricular extrasystoles. </paragraph><paragraph>^cAbdominal pain/dyspepsia includes abdominal pain, abdominal distension, dyspepsia, gastric disorder, and related terms </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold">Adverse Reaction Types</content></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">N= 84</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Nausea/Vomiting</td><td styleCode=" Botrule Toprule Lrule Rrule">25 (30%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Hypokalemia</td><td styleCode=" Botrule Toprule Lrule Rrule">24 (29%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Systemic hypertension</td><td styleCode=" Botrule Toprule Lrule Rrule">20 (24%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hemorrhage/Contusion ^a</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">19 (23%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Headache</td><td styleCode=" Botrule Toprule Lrule Rrule">18 (21%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Abnormal uterine bleeding</td><td styleCode=" Botrule Toprule Lrule Rrule">17 (20%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Arrhythmia ^b</td><td styleCode=" Botrule Toprule Lrule Rrule">16 (19%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Fatigue</td><td styleCode=" Botrule Toprule Lrule Rrule">15 (18%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Upper respiratory infection</td><td styleCode=" Botrule Toprule Lrule Rrule">15 (18%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Abdominal pain/Dyspepsia ^c</td><td styleCode=" Botrule Toprule Lrule Rrule">13 (15%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dizziness</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>13 (15%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Diarrhea</td><td styleCode=" Botrule Toprule Lrule Rrule">13 (15%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Decreased appetite</td><td styleCode=" Botrule Toprule Lrule Rrule">11 (13%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dry mouth</td><td styleCode=" Botrule Toprule Lrule Rrule">9 (11%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Dry skin</td><td styleCode=" Botrule Toprule Lrule Rrule">9 (11%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Adrenal insufficiency</td><td styleCode=" Botrule Toprule Lrule Rrule">8 (10%)</td></tr></tbody></table>

<table><caption>Table 3: Adverse Reactions, Excluding Hepatic Injury, Occurring in &#x2265;10% of Cushing&#x2019;s Syndrome Patients Treated with RECORLEV in Study 2</caption><col/><col/><tfoot><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event.</paragraph><paragraph>^aErythema includes flushing. </paragraph><paragraph>^bHemorrhage/Contusion includes blood urine present, conjunctival hemorrhage, ecchymosis, epistaxis, hematoma, hyphemia, and red blood cells urine. </paragraph><paragraph>^cAbdominal pain/dyspepsia includes abdominal discomfort, abdominal distension, dyspepsia, gastritis, and other related terms. </paragraph><paragraph>^dArrhythmia includes bradycardia, carotid pulse increased, defect conduction intraventricular, electrocardiogram QT prolonged, electrocardiogram T wave abnormal, heart rate increased, palpitations and sinus bradycardia. </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Adverse Reaction Type</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">N = 94</content></paragraph><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Erythema ^a</td><td styleCode=" Botrule Toprule Lrule Rrule">40 (43%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hemorrhage/Contusion ^b</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">38 (40%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Fatigue</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">37 (39%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Headache</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">36 (38%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nausea/Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">35 (37%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abdominal pain/dyspepsia ^c</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">31 (33%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arthritis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">26 (28%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Upper respiratory infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">26 (28%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Myalgia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">24 (26%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Abnormal uterine bleeding</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">23 (24%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Arrhythmia ^d</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">23 (24%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Back pain</td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>21 (22%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Insomnia/Sleep disturbances</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">21 (22%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Peripheral edema</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">19 (20%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Systemic hypertension</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">19 (20%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Diarrhea</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">18 (19%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pre-Syncope/Syncope</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">17 (18%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Rash</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">16 (17%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">15 (16%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hypokalemia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">14 (15%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pruritus</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">14 (15%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Disturbance in attention</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">13 (14%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Irritability</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">13 (14%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Depression</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">11 (12%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Dry skin</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">11 (12%)</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Alopecia</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">10 (11%)</td></tr></tbody></table>

<table><caption>Table 4: Hepatic Injury and Other Liver-Related Adverse Reactions Occurring in Cushing&#x2019;s Syndrome Patients Treated with RECORLEV in Studies 1 and 2</caption><col/><col/><tfoot><tr><td colspan="2" styleCode=" Botrule Toprule Lrule Rrule"><paragraph>N = total number of patients, n = number of patients experiencing the event, (%) = proportion of patients experiencing the event.</paragraph><paragraph>^aLiver enzyme elevation refers to elevation in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or gamma-glutamyl transferase. </paragraph></td></tr></tfoot><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"/><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">N = 166</content></paragraph><content styleCode="bold">n (%)</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>At least one liver related adverse reaction</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>45 (27%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Liver enzyme elevation ^a</td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>33 (20%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule">Drug-induced liver injury</td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (2%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hepatic pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7 (4%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Hepatic steatosis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Liver disorders</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (2%)</paragraph></td></tr></tbody></table>