Recorlev Drug Information
Generic name: LEVOKETOCONAZOLE
Cortisol Synthesis Inhibitor [EPC]
Uses of 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 Limitations of Use RECORLEV is not approved for the treatment of fungal infections
Dosage & Administration of Recorlev
| ≥ 5 x ULN | Any value | ≥ 3 x ULN | > 2 x ULN | ≤ 2 x ULN | > ULN to <3 x ULN | Any value | |
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Side Effects of Recorlev
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 . 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 . 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.
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
Warnings & Cautions for Recorlev
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 . Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV . Prompt recognition of liver injury is essential. At baseline, obtain liver tests . During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration . 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. 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 . If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.
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 . 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). 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 . 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 .
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 . 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 . 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 . 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 . 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.
Hypersensitivity Reactions Hypersensitivity reactions have been reported in 1% of patients treated
with RECORLEV in the clinical trials . Anaphylaxis has been reported after a single dose of oral ketoconazole. Hypersensitivity reactions including urticaria have also been reported for ketoconazole. RECORLEV is contraindicated in patients with a known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV.
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.
Drug Interactions with Recorlev
Effect of
RECORLEV on Other Drugs Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. Concomitant use of RECORLEV with drugs that are substrates of these CYP enzymes and transporters may increase the risk of adverse reactions of these drugs. Consult the approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE1 prior to initiating therapy with RECORLEV. Table 6 presents drugs affected by RECORLEV that are contraindicated or not recommended for use during RECORLEV use.
It also includes the clinical impact and management recommendations for concomitant use of RECORLEV with atorvastatin and metformin. Table 6: Effect of RECORLEV on CYP3A4 and Transporter Substrates a The drugs listed are substrates for CYP3A4 and/or P-gp. Other metabolism and/or transporter pathways may also contribute to elimination of the substrate drug.
Consult the approved product labeling for the substrate drug for more information. b Strong CYP3A4 inhibitor . c Based on clinical drug interaction study with levoketoconazole. CYP3A4 or CYP3A4 and P-gp Substrates a That May Prolong QT Clinical Impact Increases risk of QT prolongation and torsades de pointes. Prevention or Management Concomitant use of RECORLEV with other drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes, is contraindicated.
Examples Bosutinib, cisapride, clarithromycin b, cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat (in patients that are poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors), ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine. Sensitive CYP3A4 or CYP3A4 and P-gp Substrates a Clinical Impact Increases plasma concentrations of the substrate and may increase the risk of the substrate’s adverse reactions. Prevention or Management Concomitant use of RECORLEV with sensitive CYP3A4 or CYP3A4 and P-gp substrate drugs is contraindicated or not recommended . Refer to the prescribing information of the substrate drug.
Examples Alfentanil, avanafil, buspirone, conivaptan b, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir b, triazolam, and vardenafil. CYP3A4 Substrate Atorvastatin c Clinical Impact Increases plasma concentration of atorvastatin c and may increase the risk of atorvastatin-associated myopathy and rhabdomyolysis . Prevention or Management Concomitant use of RECORLEV with atorvastatin may require a dose reduction of atorvastatin. Use the lowest atorvastatin dose possible and monitor for adverse reactions when atorvastatin dosage exceeds 20 mg daily.
OCT2 and MATE Substrate Metformin c Clinical Impact Increases plasma concentration of metformin c and may increase the risk of metformin’s adverse reactions . May increase plasma concentrations of other OCT2 and MATE substrates and increase the risk of their adverse reactions. Prevention or Management During RECORLEV dosage titration, monitor glycemia, kidney function, and Vitamin B12 in blood as per metformin prescribing information and adjust the dosage of metformin as needed.
Effect of Other Drugs on
RECORLEV Table 7 presents clinically significant drug interactions that affect RECORLEV. Table 7: Clinically Significant Drug Interactions (Drugs that Affect RECORLEV) Strong CYP3A4 Inhibitors Clinical Impact May increase plasma concentrations of levoketoconazole and increase the risk of adverse reactions from RECORLEV . Prevention or Management Administration of strong enzyme inhibitors of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV. Examples Antivirals (e.g., ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, saquinavir) Glucocorticoid and progesterone receptor antagonists (e.g., mifepristone) Strong CYP3A4 Inducers Clinical Impact May decrease plasma concentrations of levoketoconazole and reduce the efficacy of RECORLEV Prevention or Management Administration of strong enzyme inducers of CYP3A4 with RECORLEV is not recommended. Avoid use of these drugs from 2 weeks before and during treatment with RECORLEV. Examples Antibacterials (e.g., isoniazid, rifabutin, rifampicin) Anticonvulsants (e.g., carbamazepine, phenytoin) Antivirals (e.g., efavirenz, nevirapine) Cytotoxic agents (e.g., mitotane) Gastric Acid Neutralizers Clinical Impact Impairs absorption of levoketoconazole from RECORLEV. Prevention or Management Take gastric acid neutralizers a minimum of 2 hours after dosing with RECORLEV. Examples Aluminum hydroxide Gastric Acid Suppressors Clinical Impact Impairs absorption of levoketoconazole from RECORLEV. Prevention or Management Avoid use of gastric acid suppressors with RECORLEV. Examples H2-receptor antagonists and proton pump inhibitors Sucralfate Clinical Impact Impairs absorption of levoketoconazole from RECORLEV. Prevention or Management Avoid use of sucralfate with RECORLEV.
Alcohol Patients should be advised against excessive alcohol consumption while using
RECORLEV . When used with alcohol cases of a disulfiram-like reaction have been reported with ketoconazole characterized by flushing, rash, peripheral edema, nausea, and headache. All symptoms completely resolved within a few hours.
Contraindications for 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 . Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes . 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) . With known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV . Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gP . Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 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 Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome Hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp
Overdosage Information for Recorlev
In the event of acute accidental overdose, treatment consists of supportive and symptomatic measures. Within the first hour after ingestion, activated charcoal may be administered.
Clinical Studies of Recorlev
The effectiveness of RECORLEV in patients with Cushing's syndrome was evaluated in two studies, Study 1 and Study 2. Study 1 Study 1 consisted of an open-label dose titration and maintenance phase of up to 19 weeks duration, followed by an 8-week double-blind, placebo-controlled, randomized withdrawal phase ( NCT03277690 ). Study 1 enrolled 84 Cushing’s syndrome patients with persistent or recurrent disease despite surgery, previously medically treated patients, and previously untreated patients. The etiology of Cushing's syndrome was Cushing's disease for 70 (83%) patients, adrenal Cushing’s syndrome in 8 (10%) patients, ectopic ACTH secretion for 2 (2%) patients, and unknown for 4 (5%) patients. Patients with pituitary or adrenal carcinoma were excluded.
Twelve (14%) patients who had previously received RECORLEV in Study 2 were also enrolled in Study 1. The mean age at baseline was 45 years; 76% of patients were female. Overall, the mean time since diagnosis was 63 months before treatment with the first dose in this study. Persistence or recurrence of Cushing’s syndrome was evidenced by the mean of three 24-hour UFC levels greater than or equal to 1.5 × upper limit of normal (normal range: 11 to 138 nmol/day or 4 to 50 µg/day). For the 79 patients who underwent dose titration, the mean mUFC (SD) at study baseline was 785 nmol/day, which corresponds to approximately 6 × ULN. The median mUFC at baseline was 479 nmol/day, which corresponds to approximately 3.5 × ULN. Seventy-two patients were naïve to treatment with RECORLEV, seven patients were treated with RECORLEV in Study 2 but were not on therapeutic dose (dose at which mUFC level was ≤ ULN, or maximum allowed dose had been reached, or a clinically meaningful partial response based on clinical judgement, and the maximum tolerated dose had been reached) prior to the enrollment in Study 1. Five of 84 patients continued treatment with therapeutic dose of RECORLEV prior to the enrollment in Study 1; these patients were enrolled directly in the randomized withdrawal phase.
Dose Titration and Maintenance Phase (14-19 weeks) Seventy-nine patients entered the dose titration and maintenance phase. Patients naïve to treatment with RECORLEV were started on 150 mg of RECORLEV orally twice daily. Patients who previously participated in Study 2 could start on a dose higher than 150 mg twice daily.
The dose could be titrated in 150-mg increments at 2-week intervals to a maximum of 600 mg twice daily to achieve mUFC within the normal range. The dose was increased if mUFC was above ULN and was reduced based on individual tolerability. Patients who achieved a stable therapeutic dose for at least 4 weeks and achieved a normal mUFC at the end of the dose titration and maintenance phase were eligible for the randomized withdrawal phase.
Randomized Withdrawal Phase (approximately 8 weeks) Forty-four patients entered the randomized withdrawal phase: 39 patients from dose titration and maintenance phase and 5 patients directly from Study 2. Patients were randomized in a 1:1 ratio to either continue RECORLEV or receive matched placebo for approximately 2 months or until early rescue was necessary (i.e., for mUFC >1.5 × ULN). Efficacy Assessment and Results The key secondary efficacy endpoint was the proportion of patients with mUFC normalization, defined as a patient with mUFC at or below the ULN at the end of randomized withdrawal phase without meeting a requirement for early rescue during the randomized withdrawal phase. Out of the 79 patients who entered the dose titration and maintenance phase, 37 (47%) patients who met the requirement to be on a stable therapeutic dose for at least 4 weeks and established normal mUFC at the end of the dose titration and maintenance phase, and 2 patients who did not meet the requirement due to abnormal mUFC, continued to the randomized-withdrawal phase. Out of 5 patients from Study 2 who were enrolled directly in the randomized withdrawal phase, 2 patients had normal mUFC. Among the 39 patients who had normal mUFC at the randomized withdrawal phase baseline, 21 were randomized to the RECORLEV group and 18 to the placebo group.
The number and percent of patients who had normal mUFC at the end of the randomized withdrawal phase was 11/21 (52.4%) in RECORLEV group and 1/18 (5.6%) in placebo group, and the treatment difference (CI) was 46.8% (16.5%, 70.2%). Out of 11 patients with normal mUFC at the end of the randomized-withdrawal phase, 7 patients in the RECORLEV group had normal mUFC throughout the randomized-withdrawal phase. Figure 1 depicts the mUFC during the randomized-withdrawal phase of Study 1. The line for the placebo group should be interpreted with caution as majority of placebo patients were rescued early due to high mUFC levels and were not included in the analysis. Figure 1: Line Plot of the Mean Urinary Free Cortisol During the Randomized Withdrawal Phase of Study 1 - Observed Mean (± SE) mUFC = Mean Urinary Free Cortisol; RW = Randomized Withdrawal; SE = Standard Error; ULN = Upper Limit of Normal Only patients who remained in study with non-missing mUFC are included in the analysis Study 2 Supportive evidence of efficacy was obtained from Study 2 which was a multicenter, single-arm, open-label study that consisted of three study phases (dose titration, maintenance, and extended evaluation) for a total estimated treatment duration of up to 73 weeks ( NCT01838551 ) Study 2 enrolled 94 Cushing’s syndrome patients naïve to the treatment with RECORLEV with persistent or recurrent disease despite surgery, previously medically treated patients, and previously untreated patients.
The etiology of Cushing's syndrome was benign pituitary adenoma for 80 (85%) patients, adrenal Cushing’s syndrome in 8 (9%) patients, ectopic ACTH secretion for 1 (1%) patient, and unknown source for 5 (5%) patients. Patients with pituitary or adrenal carcinoma were excluded. The mean age at enrollment was 44 years; 82% of patients were female.
Overall, the mean time since diagnosis was 68 months before treatment with the first dose in this study. Persistence or recurrence of Cushing’s syndrome was evidenced by the mean of four 24-hour UFC (mUFC) levels greater than or equal to 1.5 times upper limit of normal (ULN); normal range: 11 to 138 nmol/day or 4 to 50 µg/day). The mean (SD) of the mean urinary free cortisol (mUFC) at baseline was 243 µg/day, which corresponds to approximately 5 x ULN. The median mUFC at baseline was 148 µg/day (range 59-1510), which corresponds to approximately 3 x ULN. Dose Titration Phase (2 to 21 weeks) Ninety-four patients received a starting dosage of 150 mg RECORLEV orally twice daily that was titrated approximately every 2 to 3 weeks if mUFC was above the ULN to a maximum of 600 mg twice daily. Patients who achieved a therapeutic dose were continued to the maintenance phase.
Therapeutic dose was defined as a dose at which mUFC level was ≤ ULN, or maximum allowed dose (600 mg twice daily) had been reached, or a clinically meaningful partial response based on clinical judgement, and the maximum tolerated dose had been reached. Maintenance Phase (6 months) Seventy-seven patients who achieved a therapeutic dose in the dose titration phase entered the maintenance phase and continued treatment with therapeutic dose of RECORLEV for 6 months. The dose of RECORLEV was allowed to be decreased for safety or tolerability reasons or increased for loss of efficacy.
The primary efficacy endpoint was evaluated at the end of maintenance phase. Extended Evaluation Phase (6 months) Sixty patients entered the extended evaluation phase in which treatment with RECORLEV continued for an additional 6 months. Efficacy Assessment and Results The primary efficacy endpoint of the study was the proportion of patients with normalization of mUFC at the end of the 6-month maintenance phase.
Normalization of mUFC was defined as mUFC at or below the ULN based on central laboratory result without requiring a dose increase during the maintenance phase. At the end of the maintenance phase, 29 of 94 patients (30.9%, 95% exact confidence interval 21.7%, 41.2%) met the primary endpoint. Out of the 94 patients who enrolled in Study 2, 63 (67%) patients had normal mUFC at the end of the titration phase, 29 (30.9%) patients had normal mUFC at the end of the maintenance phase without any dose increase during the maintenance phase, and 16 (17%) patients had normal mUFC at the end of the extended evaluation phase without dose increase during maintenance or extended evaluation phase.
However, because 51% of patients discontinued treatment prematurely due to adverse reaction, lack of efficacy, or other reasons, these results should be interpreted with caution. Figure 1
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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