Isturisa

5 WARNINGS AND PRECAUTIONS Hypocortisolism : Monitor patients closely for hypocortisolism and potentially life-threatening adrenal insufficiency. Dosage reduction or interruption may be necessary. After interruption or discontinuation of ISTURISA, cortisol suppression may persist and patients should be regularly monitored ( 5.1 ) QTc Prolongation : Perform electrocardiogram in all patients Use with caution in patients with risk factors for QTc prolongation ( 5.2 ) Elevations in Adrenal Hormone Precursors and Androgens: Monitor for hypokalemia, worsening of hypertension, edema, and hirsutism ( 5.3 ) 5.1 Hypocortisolism ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia [see Adverse Reactions (6) ] . Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.). Monitor 24-hour urine free cortisol, serum or plasma cortisol, and patient's signs and symptoms periodically during ISTURISA treatment. Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After interruption or discontinuation of ISTURISA, cortisol suppression may persist beyond the 4 hour half-life. Monitor patients regularly and re-initiate ISTURISA at a lower dose when urine free cortisol, serum or plasma cortisol levels are within target range, and/or patient symptoms have resolved. Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur. 5.2 QTc Prolongation ISTURISA is associated with a dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Correct electrolyte abnormalities if indicated. Consider temporary discontinuation of ISTURISA in the case of an increase in QTc interval > 480 ms. Use caution in patients with risk factors for QT prolongation, (such as congenital long QT syndrome, congestive heart failure, bradyarrhythmias, uncorrected electrolyte abnormalities, and concomitant medications known to prolong the QT interval) and consider more frequent ECG monitoring. 5.3 Elevations in Adrenal Hormone Precursors and Androgens ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens. Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension [see Adverse Reactions (6) ] . Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. ISTURISA-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists. ISTURISA dose reduction or discontinuation may be necessary. Accumulation of androgens may lead to hirsutism, hypertrichosis and acne (in females). Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur.

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Hypocortisolism [see Warnings and Precautions (5.1) ] QT Prolongation [see Warnings and Precautions (5.2) ] Elevations in Adrenal Hormone Precursors and Androgens [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence > 20%) are adrenal insufficiency, fatigue, nausea, headache, edema, decreased appetite, arthralgia, myalgia, and diarrhea ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 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 clinical trials of another drug and may not reflect the rates observed in practice. The safety of ISTURISA was evaluated in two clinical trials in adults with Cushings disease. Study 1 (NCT02180217) was a 4-period, multicenter study with a 12-week open-label titration period, 12-week open-label maintenance period, 8-week double-blind, placebo-controlled period, and 14 to 24-week open label treatment period in 137 patients with Cushing's disease. Study 2 (NCT02697734) was a 2-period, multicenter study with a 12-week randomized, double-blind, placebo-controlled period and a 36-week open-label treatment period in 74 patients with Cushing's disease [see Clinical Studies (14) ] . Study 1 The adverse reactions that occurred with frequency higher than 10% during the core 48-week period are shown in Table 1. Table 1: Adverse Reactions With a Frequency of More Than 10% in 48-week Clinical Study 1 in Adults with Cushing's Disease Adverse Reaction Type (N = 137) % Adrenal insufficiency Adrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, cortisol decreased. One-third of the subjects with this event had low cortisol levels indicative of Adrenal Insufficiency. The majority of subjects had normal cortisol levels suggesting a cortisol withdrawal syndrome. 43.1 Fatigue Fatigue includes lethargy, asthenia. 38.7 Nausea 37.2 Headache Headache includes head discomfort. 30.7 Edema Edema includes edema peripheral, generalized edema, localized edema. 21.2 Nasopharyngitis 19.7 Vomiting 19 Arthralgia 17.5 Back pain 15.3 Rash Rash includes rash erythematous, rash generalized, rash maculopapular, rash papular. 15.3 Diarrhea 14.6 Blood corticotrophin increased 13.9 Dizziness Dizziness includes dizziness postural. 13.9 Abdominal pain Abdominal pain includes abdominal pain upper, abdominal discomfort 13.1 Hypokalemia Hypokalemia includes blood potassium decreased. 12.4 Myalgia 12.4 Decreased appetite 11.7 Hormone level abnormal 11.7 Hypotension Hypotension includes orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. 11.7 Urinary tract infection 11.7 Blood testosterone increased 10.9 Pyrexia 10.9 Anemia 10.2 Cough 10.2 Hypertension 10.2 Influenza 10.2 Other notable adverse reactions which occurred with a frequency less than 10% were: hirsutism (9.5%), acne (8.8%), dyspepsia (8%), insomnia (8%), anxiety (7.3%), depression (7.3%), gastroenteritis (7.3%), malaise (6.6%), tachycardia (6.6%), alopecia (5.8%), transaminases increased (4.4%), electrocardiogram QT prolongation (3.6%), and syncope (1.5%). Description of Select Adverse Reactions from the Core 48-week Period of Study 1 Gastrointestinal Disorders Gastrointestinal disorders, predominantly nausea, vomiting, diarrhea and abdominal pain were reported in 69% of patients. In many cases, the episodes were of short duration (1-2 days) and the severity was mild to moderate. Hypocortisolism Hypocortisolism was reported at a rate of 31% up to 12 weeks, and 18% from Weeks 12 to 26. The majority of cases were manageable by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy . Changes in Pituitary Tumor Volume An increase in the pituitary corticotroph tumor volume by greater than 20% from baseline was observed in 21/137 (15%) patients, while a decrease in tumor volume by greater than 20% from baseline was observed in 24/137 (18%) patients at Week 48. Eight patients discontinued because of an increase in tumor volume. There was no correlation between tumor volume increase and increase in adrenocorticotrophic hormone (ACTH). There was no specific pattern of timing of the tumor volume increase and no relationship with the total and the last dose of ISTURISA used in the study. QTc Interval Prolongation Adverse reactions of QT prolongation and clinically relevant ECG findings were reported. Five (4%) patients had an event of QT prolongation, 3 (2%) patients had a QTcF increase of > 60ms from baseline, and 18 (13%) had a new QTcF value of > 450ms [see Clinical Pharmacology (12.2) ] . Accumulation of Adrenal Hormone Precursors CYP11B1 inhibition by ISTURISA is associated with adrenal steroid precursor accumulation and testosterone increases [see Warnings and Precautions (5.3) ] . The incidence of adverse reactions potentially related to accumulation of adrenal hormone precursors was 42%. Hypertension and hypokalemia were the most common adrenal hormone precursor-related adverse reactions and occurred in 14% of patients and 17% of patients, respectively; edema was reported in 7% of patients, elevated blood pressure in 15% of patients. All cases of hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone). One patient discontinued the study because of hypokalemia. In male patients testosterone levels generally increased but remained within normal limits; all patients were asymptomatic with no values above upper limit of normal (ULN) at last available value. In female patients, mean testosterone levels increased above the normal range from baseline and reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism (12%) or acne (11%) in a subset of female patients. Other Abnormal Laboratory Findings Decreased Absolute Neutrophil Count Of the 137 patients from the 48-week study 1, 18 patients had at least one measured absolute neutrophil count below the normal limit, 2 patients had an adverse reaction of neutropenia. No concomitant infections and/or fever were reported in patients with decreased absolute neutrophil count. Elevated Liver Function Tests Liver enzyme elevations in patients treated with ISTURISA were infrequent, typically mild and reversed spontaneously or following dose adjustment. Most liver abnormal parameters occurred during the dose-titration period and no patients discontinued ISTURISA drug due to abnormal liver chemistry parameters. Five (4%) patients had ALT or AST > 3 × ULN during the 48-week clinical study. Study 2 The adverse reactions that occurred with frequency higher than 10% and greater than placebo during the 12-week placebo controlled period are shown in Table 2. Table 2: Adverse Reactions With a Frequency of More Than 10% and Greater Than Placebo in the 12-week Placebo Controlled Period of Clinical Study 2 in Adults with Cushing's Disease Adverse Reaction Type ISTURISA (N = 48) % Placebo (N=25) % Decreased appetite 38 16 Arthralgia 35 12 Nausea 31 12 Fatigue fatigue includes asthenia, fatigue, and malaise 29 16 Myalgia myalgia includes myalgia and fibromyalgia 23 4 Diarrhea 21 0 Dizziness 19 16 Adrenal insufficiency 15 0 Tachycardia tachycardia includes tachycardia and sinus tachycardia 15 0 Nasopharyngitis nasopharyngitis includes upper respiratory tract infection, nasopharyngitis, and pharyngitis 15 4 Hypotension hypotension includes hypotension and orthostatic hypotension 15 0 Pruritus 13 0 Abdominal pain abdominal pain includes abdominal pain, abdominal pain upper, and gastrointestinal pain 13 4 Renal and urinary tract infection renal and urinary tract infection includes urinary tract infection and cystitis 13 0 Peripheral edema peripheral edema includes edema peripheral and peripheral swelling 10 4 Viral infection viral infection includes Influenza, conjunctivitis viral, Dengue fever, and oral herpes 10 0 Vomiting 10 0 Blood testosterone increased 10 0 Description of Selected Adverse Reactions from the 12-week Placebo-Controlled Period of Study 2 Hypocortisolism Hypocortisolism was reported at a rate of 15% in ISTURISA arm and no subjects in placebo arm. The majority of cases were manageable by interrupting/reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy . QTc Interval Prolongation One (2%) patient in ISTURISA arm had a new QTcF value of > 450ms versus none in placebo arm . Accumulation of Adrenal Hormone Precursors CYP11B1 inhibition by ISTURISA is associated with adrenal steroid precursor accumulation and testosterone increases [see Warnings and Precautions (5.3) ] . The incidence of adverse reactions potentially related to accumulation of adrenal hormone precursors was 44% in ISTURISA arm and 36% in placebo arm. Hypertension, blood testosterone increase, peripheral edema, acne and hypokalemia were the most common adrenal hormone precursor-related adverse reactions and occurred in 17% 10%, 10%, 4% and 2% of patients in ISTURISA arm, and in 32%, 0%, 4%, 0% and 0% of patients in the placebo arm. Most cases of hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone). One patient discontinued the study because of hypokalemia. Other Abnormal Laboratory Findings Decreased Absolute Neutrophil Count Three (6%) patients in ISTURISA arm had at least one measured absolute neutrophil count below the normal limit and one (2%) of these was classified as Grade 3 by Common Terminology Criteria for Adverse Events (CTCAEs) grading. No patients in placebo arm had absolute neutrophil count below normal limit. Elevated Liver Function Tests Liver enzyme elevations in patients treated with ISTURISA were infrequent, typically mild and reversed spontaneously. No patient had concurrent increases in AST, ALT and total bilirubin and/or ALP. No patient met the criteria for Hy's Law. Two (4%) patients in ISTURISA arm versus none in placebo arm had ALT or AST > 3 × ULN. 6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of ISTURISA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neutropenia associated with fever and infection

<table width="75%"><caption>Table 1: Adverse Reactions With a Frequency of More Than 10% in 48-week Clinical Study 1 in Adults with Cushing&apos;s Disease </caption><col width="60%" align="left" valign="middle"/><col width="40%" align="left" valign="bottom"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule">Adverse Reaction Type</th><th styleCode="Rrule" valign="middle">(N = 137) %</th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule">Adrenal insufficiency<footnote>Adrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, cortisol decreased. One-third of the subjects with this event had low cortisol levels indicative of Adrenal Insufficiency. The majority of subjects had normal cortisol levels suggesting a cortisol withdrawal syndrome.</footnote></td><td styleCode="Rrule">43.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Fatigue<footnote>Fatigue includes lethargy, asthenia.</footnote></td><td styleCode="Rrule">38.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">37.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Headache<footnote>Headache includes head discomfort. </footnote></td><td styleCode="Rrule">30.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Edema<footnote>Edema includes edema peripheral, generalized edema, localized edema.</footnote></td><td styleCode="Rrule">21.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">19.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">19</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">17.5</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">15.3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Rash<footnote>Rash includes rash erythematous, rash generalized, rash maculopapular, rash papular.</footnote></td><td styleCode="Rrule">15.3</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">14.6</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Blood corticotrophin increased</td><td styleCode="Rrule">13.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Dizziness<footnote>Dizziness includes dizziness postural.</footnote></td><td styleCode="Rrule">13.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Abdominal pain<footnote>Abdominal pain includes abdominal pain upper, abdominal discomfort</footnote></td><td styleCode="Rrule">13.1</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Hypokalemia<footnote>Hypokalemia includes blood potassium decreased.</footnote></td><td styleCode="Rrule">12.4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">12.4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">11.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Hormone level abnormal</td><td styleCode="Rrule">11.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Hypotension<footnote>Hypotension includes orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased.</footnote></td><td styleCode="Rrule">11.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">11.7</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Blood testosterone increased</td><td styleCode="Rrule">10.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" valign="bottom">Pyrexia</td><td styleCode="Rrule">10.9</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" valign="bottom">Anemia</td><td styleCode="Rrule">10.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" valign="bottom">Cough</td><td styleCode="Rrule">10.2</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule" valign="bottom">Hypertension</td><td styleCode="Rrule">10.2</td></tr><tr><td styleCode="Lrule Rrule" valign="bottom">Influenza</td><td styleCode="Rrule">10.2</td></tr></tbody></table>

<table width="75%"><caption>Table 2: Adverse Reactions With a Frequency of More Than 10% and Greater Than Placebo in the 12-week Placebo Controlled Period of Clinical Study 2 in Adults with Cushing&apos;s Disease</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="left" valign="bottom"/><col width="30%" align="left" valign="bottom"/><thead><tr styleCode="botrule"><th styleCode="Lrule Rrule">Adverse Reaction Type</th><th styleCode="Rrule">ISTURISA (N = 48) %</th><th styleCode="Rrule">Placebo (N=25) %</th></tr></thead><tbody><tr styleCode="botrule"><td styleCode="Lrule Rrule">Decreased appetite</td><td styleCode="Rrule">38</td><td styleCode="Rrule">16</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">35</td><td styleCode="Rrule">12 </td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">31</td><td styleCode="Rrule">12</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Fatigue <footnote>fatigue includes asthenia, fatigue, and malaise</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">16</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Myalgia <footnote>myalgia includes myalgia and fibromyalgia</footnote></td><td styleCode="Rrule">23</td><td styleCode="Rrule">4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">21</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">19</td><td styleCode="Rrule">16</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Adrenal insufficiency</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Tachycardia <footnote>tachycardia includes tachycardia and sinus tachycardia</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Nasopharyngitis <footnote>nasopharyngitis includes upper respiratory tract infection, nasopharyngitis, and pharyngitis</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Hypotension <footnote>hypotension includes hypotension and orthostatic hypotension</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Abdominal pain <footnote>abdominal pain includes abdominal pain, abdominal pain upper, and gastrointestinal pain</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Renal and urinary tract infection <footnote>renal and urinary tract infection includes urinary tract infection and cystitis</footnote></td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Peripheral edema <footnote>peripheral edema includes edema peripheral and peripheral swelling</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">4</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Viral infection <footnote>viral infection includes Influenza, conjunctivitis viral, Dengue fever, and oral herpes</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr styleCode="botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Blood testosterone increased</td><td styleCode="Rrule">10</td><td styleCode="Rrule">0</td></tr></tbody></table>