recorlev

Obtain baseline liver and electrocardiogram tests and correct hypokalemia and hypomagnesemia before starting RECORLEV ( 2.1 ) Initiate dosage at 150 mg orally twice daily, with or without food. Titrate dosage by 150 mg daily, no more frequently than every 2-3 weeks ( 2.2 ) Maximum recommended dosage is 1200 mg daily, administered as 600 mg twice daily ( 2.2 ) For additional recommendations on titration and monitoring for efficacy, see Full Prescribing Information ( 2.2 ) For recommendations on safety monitoring and dosage modifications for hepatotoxicity, QT prolongation and hypocortisolism, see Full Prescribing Information ( 2.3 , 2.4 ) 2.1 Laboratory Testing Prior to RECORLEV Initiation Obtain baseline liver tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin]. Carefully consider the risks and potential benefits of initiating RECORLEV in patients with AST or ALT above normal but less than or equal to 3 times the upper limit of normal [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. Obtain baseline electrocardiogram (ECG) [see Contraindications ( 4 ), Warnings and Precautions ( 5.2 )]. Correct hypokalemia and hypomagnesemia prior to starting RECORLEV [see Warnings and Precautions ( 5.2 )]. 2.2 Recommended Dosage, Titration, and Monitoring for Efficacy Initiate dosage at 150 mg orally twice daily, with or without food [see…

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…

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 )

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.

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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 [see Warnings and Precautions ( 5.1 )] . 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.