Osilodrostat

Osilodrostat should be used with caution and the benefit-risk carefully weighed in patients with risk factors for QT prolongation such as:

• congenital long QT syndrome,
• significant cardiovascular disease (including congestive heart failure, recent myocardial infarction, unstable angina, sustained ventricular tachycardia, advanced heart block and clinically significant bradyarrhythmias), and
• concomitant medicinal products known to prolong the QT interval.

If osilodrostat is used in patients with these risk factors, more frequent ECG monitoring is recommended.

Because osilodrostat and its major metabolite M34.5 may inhibit and/or induce multiple enzymes and transporters, general caution is advised when osilodrostat is co-administered with sensitive enzyme or transporter substrates with a narrow therapeutic index.

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh A). For patients with moderate hepatic impairment (Child-Pugh B), the recommended starting dose is 1 mg twice daily. For patients with severe hepatic impairment (Child-Pugh C), the recommended starting dose is 1 mg once daily in the evening, with initial up-titration to 1 mg twice daily.

Data on use in patients with hepatic impairment is limited. More frequent monitoring of adrenal function may be required in patients with hepatic impairment during dose titration.

Caution and closer monitoring are advised when co-administered medicinal products that strongly inhibit or induce multiple enzymes are introduced or discontinued during osilodrostat treatment, as they may affect osilodrostat exposure and may result in a risk of adverse events (due to a potential increase in exposure) or of decreased efficacy (due to a potential decrease in exposure).

Urinary free cortisol (UFC) levels should be interpreted with caution in patients with moderate to severe renal impairment, due to reduced UFC excretion. Alternative methods for cortisol monitoring should be considered in these patients.

Discontinuation of osilodrostat treatment should be considered in patients who develop MRI-verified corticotroph tumour invasiveness during treatment.

There are no or limited amount of data from the use of osilodrostat in pregnant women. Studies in animals have shown reproductive toxicity. Osilodrostat should not be used during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether osilodrostat or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with osilodrostat and for at least one week after treatment.

Women of childbearing potential

Based on preclinical data, osilodrostat may cause foetal harm when administered to a pregnant woman. A pregnancy test before initiating treatment is recommended in women of childbearing potential. Women of childbearing potential have to use effective contraception during and for at least one week after treatment. If hormonal contraceptives other than the oral combination of ethinylestradiol and levonorgestrel are used, an additional barrier method of contraception is recommended.

Fertility

There is no information on the effect of osilodrostat on human fertility. Animal studies have shown effects on the menstrual cycle and reduced female fertility in rats.

Osilodrostat may have a minor influence on the ability to drive and use machines. Patients should be warned about the potential for dizziness and fatigue and should be advised not to drive or use machines if these symptoms occur.

Summary of the safety profile

The most frequent adverse reactions reported in the pivotal phase III study with osilodrostat were adrenal insufficiency (51%), fatigue (44%), oedema (21%), vomiting (22%), nausea (42%) and headache (34%).

The most serious adverse reaction associated with the use of osilodrostat is adrenal insufficiency.

Tabulated list of adverse reactions

Adverse drug reactions (Table) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Adverse drug reactions:

^* Some terms denote grouped term of two or more MedDRA preferred terms that were considered clinically similar. The term “adrenal insufficiency” includes the terms glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, urine free cortisol decreased, cortisol decreased.
^** Frequency “very common” in female patients.

Description of selected adverse reactions

CYP11B1 inhibition by osilodrostat is associated with adrenal steroid precursor accumulation and testosterone increases. In a clinical study with osilodrostat, mean testosterone levels in female patients increased from high normal at baseline to above the upper limit of the normal range. The increases reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism or acne in a subset of patients.

ACTH values above 10-fold upper limit of normal were observed in some Cushing’s disease patients treated with osilodrostat in the clinical studies and may be associated with cortisol values below the lower limit of normal.