LEVOKETOCONAZOLE Drug Interactions: What You Need to Know
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Drug Interactions (FDA Label)
INTERACTIONS Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating RECORLEV ( 7.1 ) Sensitive CYP3A4 or CYP3A4 and P-gp Substrates : Concomitant use of RECORLEV with these substrates is contraindicated or not recommended ( 7.1 ) Atorvastatin : Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily ( 7.1 ) Metformin : Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed ( 7.1 ) Strong CYP3A4 Inhibitors or Inducers : Avoid use of these drugs 2 weeks before and during RECORLEV treatment ( 7.2 )
Gastric Acid
Modulators : See Full Prescribing Information for recommendations regarding concomitant use with RECORLEV ( 7.2 )
7.1 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 [see Drug Interactions ( 7.2 )] . 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )].
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 [see Contraindications ( 4 )] . 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 [see Clinical Pharmacology ( 12.3 )] . 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 ( 12.3 )] . 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.
7.2 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 ( 12.3 )] . 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.
7.3 Alcohol Patients should be advised against excessive alcohol consumption while using RECORLEV <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . 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
RECORLEV is contraindicated in patients: With cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease [see Warnings and Precautions ( 5.1 )] . Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes [see Warnings and Precautions ( 5.2 )] . With a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) [see Warnings and Precautions ( 5.2 )] . With known hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV [see Warnings and Precautions ( 5.4 ), Adverse Reactions ( 6.2 )] . Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gP [see Drug Interactions ( 7.1 )] . 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 ( 4 ) Taking drugs that cause QT prolongation associated with ventricular arrhythmias, including torsades de pointes ( 4 ) Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome ( 4 ) Hypersensitivity to levoketoconazole, ketoconazole or any excipient in RECORLEV ( 4 ) Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp ( 4 )
Related Warnings
AND PRECAUTIONS Hypocortisolism : Hypocortisolism has been reported with RECORLEV. Monitor patients for hypocortisolism. Dosage reduction or interruption may be necessary ( 5.3 )
Hypersensitivity
Reactions: Hypersensitivity to RECORLEV has been reported. Anaphylaxis has been reported with oral ketoconazole ( 5.4 )
Risks
Related to Decreased Testosterone : RECORLEV may lower serum testosterone in men and women. Inform patients to report associated symptoms ( 5.5 )
5.1 Hepatotoxicity Cases of hepatotoxicity with a fatal outcome or requiring liver transplantation have been reported with the use of oral ketoconazole, the racemic mixture from which levoketoconazole is derived. Some patients had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving RECORLEV, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in 13% of patients using RECORLEV. RECORLEV is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT greater than 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Avoid concomitant use of RECORLEV with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with RECORLEV <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> . Prompt recognition of liver injury is essential. At baseline, obtain liver tests <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . During RECORLEV treatment, regularly monitor liver enzymes, with more frequent monitoring during dosage titration <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . If a liver abnormality significantly above the patient’s baseline recurs after restarting RECORLEV, permanently discontinue RECORLEV.
5.2 QT Prolongation RECORLEV is associated with dose-related QT interval prolongation. QT interval prolongation may lead to life-threatening ventricular dysrhythmias such as torsades de pointes.
During Studies
1 and 2, which excluded patients with baseline QTcF interval greater than 470 msec, 4 (2.4%) patients experienced QTcF>500 msec, and 23 (14.7%) patients experienced change-from-baseline QTcF >60 msec. Resolution typically occurred following a dosage interruption and in some cases correction of electrolyte abnormalities. RECORLEV may also elevate plasma concentrations of certain drugs known to prolong QT intervals. Prolongation of the QT interval from certain drugs can result in life-threatening ventricular dysrhythmias such as torsades de pointes [see Drug Interactions ( 7.1 , 7.2 )] . RECORLEV is contraindicated in patients taking other drugs known to cause QT interval prolongation associated with ventricular arrhythmias, including torsades de pointes, and is contraindicated in patients with a prolonged QTcF interval of greater than 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or long QT syndrome (including first-degree family history) [see Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )]. Use RECORLEV with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrhythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Obtain a baseline QT interval measurement and regularly monitor ECG for an effect on the QT interval during RECORLEV treatment. Correct hypokalemia and/or hypomagnesemia prior to RECORLEV initiation and monitor periodically during treatment [see Dosage and Administration ( 2.1 , 2.3 )] . Temporarily discontinue RECORLEV if the QTcF interval exceeds 500 msec. After the QTcF interval returns to less than 500 msec and contributing factors are corrected, re-institution of RECORLEV at a lower dose may be considered. If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV [see Dosage and Administration ( 2.4 )] .
5.3 Hypocortisolism RECORLEV lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Adrenal insufficiency was observed in 7% of patients during the clinical program of RECORLEV <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Hypocortisolism may occur at any time during RECORLEV treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc.).
Monitor
24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms periodically during RECORLEV treatment [see Dosage and Administration ( 2.3 )] . Decrease the dosage or temporarily discontinue RECORLEV if urine free cortisol or morning blood cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, or if signs and/or symptoms consistent with hypocortisolism are reported [see Dosage and Administration ( 2.4 )] . Stop RECORLEV and administer exogenous glucocorticoid replacement therapy if morning serum or plasma cortisol levels are below target range and signs and/or symptoms of adrenal insufficiency, or hypocortisolism, are present. After RECORLEV discontinuation, cortisol suppression may persist beyond the 4- to 6- hour half-life of RECORLEV. If treatment is interrupted due to hypocortisolism, re-initiate RECORLEV at a lower dosage when cortisol levels are within target ranges and patient’s signs and/or symptoms have resolved [see Dosage and Administration ( 2.4 )] . The dosage may be titrated to the previous dose associated with hypocortisolism if the reduced dosage has been well tolerated and the reduced dosage does not achieve an adequate clinical response. Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.