Recorlev

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)].

Recommended Dosage, Titration, and Monitoring for Efficacy

• Initiate dosage at 150 mg orally twice daily, with or without food [see Clinical Pharmacology ( 12.3)].
• Titrate the dosage by 150 mg daily, no more frequently than every 2-3 weeks based on 24-hour urine free cortisol levels and patient tolerability [see Dosage and Administration ( 2.4)] . Monitor cortisol levels from at least two 24-hour urine free cortisol collections every 2-3 weeks until an adequate clinical response is achieved.
• The maximum recommended dosage is 1200 mg per day, administered as 600 mg twice daily.
• The dosage may be reduced to 150 mg once daily if needed for reasons of tolerability [see Dosage and Administration ( 2.3, 2.4)].
• Once the maintenance dosage is achieved, monitor cortisol levels from at least two 24-hour urine free cortisol collections at least every 1-2 months or as indicated.
• If 24-hour urine free cortisol levels remain above the upper normal limit after treatment with the maximum recommended dosage of 1200 mg per day, or the patient cannot tolerate treatment with RECORLEV, consider discontinuing RECORLEV and switching patient to another therapy.

Monitoring for Safety

Perform the following monitoring during RECORLEV treatment. Refer to Dosage Interruptions and Modifications below for recommendations pertaining to management of liver, cortisol, or ECG abnormalities [see Dosage and Administration ( 2.4)].

Hepatotoxicity

• Serious hepatotoxicity has been reported in patients receiving RECORLEV, and therefore frequent monitoring of liver tests is recommended.
• Monitor liver enzymes and bilirubin weekly for at least 6 weeks after starting RECORLEV, every 2 weeks for the next 6 weeks, monthly for the next 3 months, and then as clinically indicated.
• After any dose interruption or dose increase, monitor on a weekly basis until a stable dosage is achieved [see Warnings and Precautions ( 5.1)].

QT Prolongation

• Conduct an ECG before each dose increase. After a stable dosage is established, monitor routinely for an effect on the QT interval.
• Monitor blood potassium and magnesium levels periodically during treatment [see Warnings and Precautions ( 5.2)].

Hypocortisolism

• Monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism periodically during RECORLEV treatment [see Warnings and Precautions ( 5.3)].

Dosage Interruptions and Modifications

Hepatotoxicity

Refer to Table 1 for management of hepatotoxicity [see Warnings and Precautions ( 5.1) ].

QT Prolongation

• Temporarily discontinue RECORLEV if the QTcF interval is longer than 500 msec.
• After correction of other possible contributing factors (e.g., hypokalemia, hypomagnesemia, use of concomitant drugs), RECORLEV may be resumed at a lower dosage when the QTcF interval returns to 500 msec or less.
• If QT interval prolongation recurs after restarting RECORLEV, permanently discontinue RECORLEV [see Warnings and Precautions ( 5.2)] .

Hypocortisolism

• Decrease the dosage or temporarily discontinue RECORLEV if urine free cortisol or morning serum or plasma 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.
• Re-initiate RECORLEV at a lower dosage when cortisol levels are within target ranges and signs and/or symptoms of hypocortisolism have resolved [see Warnings and Precautions ( 5.3)] . 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.

Missed Dose

If a dose of RECORLEV is missed, the patient should take the next dose at the regularly scheduled time.

Pregnancy

Risk Summary

Levoketoconazole is the 2S, 4R enantiomer of ketoconazole. The available published data from case series and case-control studies on the use of the racemic ketoconazole during pregnancy are insufficient to determine a drug-associated risk of major birth defects. There are no available data on ketoconazole use during pregnancy to inform the risk of miscarriage. There are risks to the mother and fetus from untreated Cushing’s syndrome (see Clinical Considerations). No animal reproduction studies have been performed with levoketoconazole. However, levoketoconazole constituted about 70% of the exposure in humans and animals after racemic ketoconazole administration. In animal reproduction studies, embryotoxic effects were observed in pregnant mice, rats and rabbits, and fetal malformations were observed in rats, following oral dosing of racemic ketoconazole during the period of organogenesis at doses equal and less than the maximum recommended human dose (MRHD), respectively (see Data). Advise pregnant women of the potential risk to a fetus and consider whether the benefits of treatment with RECORLEV outweigh the risks.

The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15−20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Active Cushing’s syndrome during pregnancy has been associated with an increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, pre-eclampsia, maternal death, miscarriage, intrauterine fetal demise, preterm birth and neonatal death).

Labor or Delivery

Dystocia (difficult labor) was noted in mice and rats administered oral ketoconazole during the period of organogenesis at exposures below the MRHD of levoketoconazole (by body surface area (BSA)). The clinical relevance of these findings for human is unknown.

Data

Animal Data

Racemic ketoconazole containing levoketoconazole was administered orally to rats, mice, and rabbits during the period of organogenesis. Levoketoconazole constituted about 70% of the exposure in animals after racemic ketoconazole administration.

Mice were administered 10, 20, and 40 mg/kg/day ketoconazole during the period of organogenesis (gestation days 6 to 18). Embryolethality (resorptions and still births) was observed at ≥ 20 mg/kg/day (below the MRHD of levoketoconazole based on BSA comparison). There was no maternal toxicity in mice up to the highest dose of 40 mg/kg/day (below the MRHD of levoketoconazole by BSA), however, females failed to deliver naturally and Cesarean examination 3 days after the due date showed increased resorptions and dead fetuses.

Rats were administered 10, 20, 40, and 80 mg/kg/day during the period of organogenesis (gestation days 6 to 18). Increased incidences of resorbed fetuses and still births were noted at ≥40 mg/kg/day (below the MRHD of levoketoconazole by BSA). Fetal malformations (oligodactyly, syndactyly, absence of metacarpal and/or metatarsal bones, and cleft palate) were noted at ≥80 mg/kg/day of ketoconazole (at the MRHD of levoketoconazole by BSA). Dystocia and prolonged gestation were observed in rats at ≥10 mg/kg/day (below the MRHD of levoketoconazole by BSA).

In rabbits, oral gavage doses of 0, 10 and 40 mg/kg/day ketoconazole were administered during the period of organogenesis (gestation days 6 through 18). Increased incidences of resorbed fetuses and still births were observed at ≥10 mg/kg/day (below MRHD of levoketoconazole by BSA).

Lactation

Risk Summary

Published data from one lactating woman show that ketoconazole is present in human milk in low amounts, with no reported adverse effects on the breastfed infant. However, these limited data are not sufficient to inform the risk to a breastfed infant with exposure to ketoconazole through breast milk. There are no data available on the effects of ketoconazole on milk production. Because of the potential for serious adverse reactions in the breastfed infant, including liver toxicity, advise patients not to breastfeed during treatment with RECORLEV and for one day (5 times the half-life) after the final dose.

Females and Males of Reproductive Potential

Infertility

RECORLEV may lower testosterone levels [see Warnings and Precautions ( 5.5)] and impair male and female fertility. Ketoconazole tablets (containing equal parts levoketoconazole and dextroketoconazole in a racemic mixture) have been demonstrated to lower serum testosterone in humans. Once therapy with ketoconazole tablets was discontinued, serum testosterone levels returned to baseline values. Testosterone levels are impaired with ketoconazole doses of 800 mg per day and abolished by 1600 mg per day. Clinical manifestations of decreased testosterone concentrations may include gynecomastia, impotence and oligospermia. In rat fertility studies, oral ketoconazole administered at doses equivalent to the MRHD of levoketoconazole by BSA during premating to implantation caused impaired fertility in male and female rats. In dog fertility studies, levoketoconazole targeted the reproductive tissues of male dogs in a dose-dependent manner with associated effects on spermatogenesis and maturation of spermatozoa. The effect was reversible upon discontinuation of treatment [see Nonclinical Toxicology ( 13.1)] .

Pediatric Use

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

Geriatric Use

Of the 166 patients in clinical trials with RECORLEV, 12 (7%) were 65 years and older, with one patient 75 years of age. Clinical studies of RECORLEV did not include sufficient number of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Renal Impairment

There is no experience with RECORLEV in patients with renal impairment. The overall pharmacokinetics of racemic ketoconazole in patients with renal impairment were not significantly different when compared with healthy subjects.

Hepatic Impairment

The use of RECORLEV is contraindicated in patients with cirrhosis, acute liver disease or poorly controlled chronic liver disease, 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 Contraindications ( 4), Warnings and Precautions ( 5.1)] .