Recorlev
Generic: LEVOKETOCONAZOLE
Basic Information
Manufacturer
Xeris Pharmaceuticals, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
d4c5fead-bc4a-fb02-e053-2a95a90ae4fc
Indications & Usage
1 INDICATIONS AND USAGE RECORLEV is indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.
Limitations of Use RECORLEV is not approved for the treatment of fungal infections.
The safety and effectiveness of RECORLEV for the treatment of fungal infections have not been established.
RECORLEV is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative ( 1 ) Limitations of Use RECORLEV is not approved for the treatment of fungal infections ( 1 )
Limitations of Use RECORLEV is not approved for the treatment of fungal infections.
The safety and effectiveness of RECORLEV for the treatment of fungal infections have not been established.
RECORLEV is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative ( 1 ) Limitations of Use RECORLEV is not approved for the treatment of fungal infections ( 1 )
Adverse Reactions
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 2 listed 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 3 listed 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 5 summarizes 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 2 and 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
( 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 2 listed 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 3 listed 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 5 summarizes 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 2 and 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