Recorlev Side Effects Center

Last updated on RxList: 7/18/2022
Recorlev Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Recorlev?

Recorlev (levoketoconazole) is a cortisol synthesis inhibitor used to treat endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

What Are Side Effects of Recorlev?

Side effects of Recorlev include:

Seek medical care or call 911 at once if you have the following serious side effects:

  • Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
  • Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheartedness, or passing out;
  • Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.

This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.

Dosage for Recorlev

The initial dose of Recorlev is 150 mg orally twice daily, with or without food. Titrate the dosage by 150 mg daily, no more frequently than every 2-3 weeks. The maximum recommended dosage of Recorlev is 1200 mg daily, administered as 600 mg twice daily.

Recorlev In Children

The safety and effectiveness of Recorlev in pediatric patients below the age of 18 have not been established.

What Drugs, Substances, or Supplements Interact with Recorlev?

Recorlev may interact with other medicines such as:

  • CYP3A4 or CYP3A4 and P-gp substrates that may prolong QT such as bosutinib, cisapride, clarithromycin, cobimetinib, crizotinib, disopyramide, dofetilide, dronedarone, eliglustat, ivabradine, methadone, midostaurin, nicardipine, pimozide, quinidine, and ranolazine,
  • sensitive CYP3A4 or CYP3A4 and P-gp substrates such as alfentanil, avanafil, buspirone, conivaptan, dabigatran etexilate, darifenacin, darunavir,
  • digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir, triazolam, and vardenafil, 
  • atorvastatin,
  • metformin,
  • strong CYP3A4 inhibitors including antivirals such as ritonavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, and saquinavir, and glucocorticoid and progesterone receptor antagonists such as mifepristone,
  • strong CYP3A4 inducers including antibacterials such as isoniazid, rifabutin, and rifampicin, anticonvulsants such as carbamazepine and phenytoin, antivirals such as efavirenz and nevirapine, and cytotoxic agents such as mitotane,
  • gastric acid neutralizers such as aluminum hydroxide, 
  • gastric acid suppressors such as H2-receptor antagonists and proton pump inhibitors, 
  • sucralfate, and 
  • alcohol.
  Tell your doctor all medications and supplements you use.

Recorlev During Pregnancy and Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant before using Recorlev; it is unknown how it might affect a fetus. There are risks to the mother and fetus from untreated Cushing’s syndrome. Because of the potential for serious adverse reactions in breastfed infants, including liver toxicity, breastfeeding is not recommended during treatment with Recorlev and for one day after final dose.

Additional Information

Our Recorlev (levoketoconazole) Tablets, Oral Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Recorlev Professional Information

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
  • QT Prolongation [see WARNINGS AND PRECAUTIONS]
  • Hypocortisolism [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Risks related to Decreased Testosterone [see WARNINGS AND PRECAUTIONS]

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].

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

Adverse Reaction Type N = 84
n (%)
Nausea/V omiting 25 (30%)
Hypokalemia 24 (29%)
Systemic hypertension 20 (24%)
Hemorrhage/Contusiona 19 (23%)
Headache 18 (21%)
Abnormal uterine bleeding 17 (20%)
Arrhythmiab 16 (19%)
Fatigue 15 (18%)
Upper respiratory infection 15 (18%)
Abdominal pain/Dyspepsiac 13 (15%)
Dizziness 13 (15%)
Diarrhea 13 (15%)
Decreased appetite 11 (13%)
Dry mouth 9 (11%)
Dry skin 9 (11%)
Adrenal insufficiency 8 (10%)
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

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

Adverse Reaction Type N = 94
n (%)
Erythemaa 40 (43%)
Hemorrhage/Contusionb 38 (40%)
Fatigue 37 (39%)
Headache 36 (38%)
Nausea/V omiting 35 (37%)
Abdominal pain/dyspepsiac 31 (33%)
Arthritis 26 (28%)
Upper respiratory infection 26 (28%)
Myalgia 24 (26%)
Abnormal uterine bleeding 23 (24%)
Arrhythmiad 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%)
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.

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 = 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%)
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.

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 = 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)
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.

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]. 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

DRUG INTERACTIONS

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

CYP3A4 or CYP3A4 and P-gp Substratesa 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 [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
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 Substratesa
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 [see CONTRAINDICATIONS]. Refer to the prescribing information of the substrate drug.
Examples Alfentanil, avanafil, buspirone, conivaptanb, dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavirb, 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 [see CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY]. 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.
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 [see DRUG INTERACTIONS].
c Based on clinical drug interaction study with levoketoconazole.

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 [see CLINICAL PHARMACOLOGY].
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.

Alcohol

Patients should be advised against excessive alcohol consumption while using RECORLEV [see WARNINGS AND PRECAUTIONS]. 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.

Read the entire FDA prescribing information for Recorlev (Levoketoconazole Tablets)

© Recorlev Patient Information is supplied by Cerner Multum, Inc. and Recorlev Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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